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The role of alfa synuclein inParkinson’s disease
I have been diagnosed in 2020 with Parkinson’s disease. My background is a MSC in Biochemistry and a PhD in Biology. After 10 years in the lab I spent most of my life on data presentation and recovery in the context of the “Semantic Web”. With the developing AI revolution I was obviously excited what this could mean for fighting PD.
I am convinced that (already the existing level) AI can revolutionize medical research development. The problem in research, but especially in biomedical research is that 1000 and 1000nds of research groups work in parallel, without real knowledge exchange. The existing system (conferences and scientific journals, individual exchanges) is not sufficient any more. the sheer amount of data is too bigto be handled by human beeings. there is also a “social” issue. Dealing with data from other, making critical reviews is not the way for young scientists to get a name , it has to be something new from the lab. AI could be one solution. An AI engine could look on ALL of PD together to find common patterns, divergence and upcoming trends.
I ask myself why this does not happen.The problem is again compartimetalization.
A good amount of medical doctors is far away from IT developments. When they ask the health history of a patient, they note it with pensil on paper. On paper are patient reports. There is very little data exchange. well meant, but badly constructed data protection rules do not help.
Scientists have a better relationship to IT, but it is mostly restricted to the use of tools to produce and elaborate their own data. I think very few would be able to use the API of openAI to make a specific interface for their area.
Better is the situation with engineers. The first AI implementations for PD are tools, mostly for early diagnosis.
I initially wanted to step into this void myselve and to develop a system, that applies AI to PD. But I quickly got convinced that I am lacking competence and scale.
But I carry on firing prompts towards my open AI suite. The last result that I got applying “Deep research”, is really remarkable. The development is as follows.
My initial prompt: “I want to know everything about the role o f alfa synuclein in the developoment of Parkinsons disease. Is there a common view that blocking agglomeration of alfa synuclein stops the disease? What is the importance aboutthe research published in Science in february 25, identifying a gene that is responsible for the agglomeration of alfa synuclein. What should be the nextsteps in the research?”
the AI answered:”I can certainly gather comprehensive information on alpha-synuclein’s role in Parkinson’s disease, the impact of blocking its aggregation, and the significance of the February 25th Science publication on a gene linked to its aggregation. To ensure I provide the most relevant details, could you clarify:
- Are you interested in a general overview of alpha-synuclein’s role or a deep dive into specific mechanisms?
- Should I focus on therapeutic approaches currently under research, including the feasibility of stopping the disease by blocking aggregation?
- Would you like an analysis of the February 25th Science paper’s findings, its implications, and expert opinions on it?
- Should I include perspectives on the next steps in research, including drug development, gene therapy, or clinical trials?
Let me know how detailed and technical you’d like the information to be!”
Me: “first question: general overview, second question: yes focus on therapeutic approaches is importatn, thirs question: yes! 4th question: yes, especially drug development and chemical trials. less gene therapy. Over all: detailed, yes , but understandable also for scientific skilled lay person”
theAI:”Got it! I will provide a detailed but understandable overview of alpha-synuclein’s role in Parkinson’s disease, focusing on:
- The general mechanisms and significance of alpha-synuclein in disease progression.
- The potential of blocking its aggregation as a therapeutic strategy, including existing and emerging treatments.
- An analysis of the February 25th Science paper, its findings, and expert interpretations.
- The next steps in research, with a strong focus on drug development and clinical trials rather than gene therapy.
I will get back to you with a comprehensive report soon!”
After half an hour I got the following piece:
Alpha-Synuclein in Parkinson’s Disease: Role, Therapeutic Targeting, and Recent Advances
1. Biological Function of Alpha-Synuclein and Parkinson’s Pathology
Alpha-synuclein (α-syn) is a small, soluble protein abundantly expressed in neurons, especially at presynaptic terminals. Under normal conditions, it helps regulate synaptic function — for example, it binds to synaptic vesicles and assists in neurotransmitter release and vesicle recycling
. α-Synuclein is natively unstructured in solution but can adopt an α-helical shape when bound to lipid membranes (such as vesicles) or form β-sheet-rich aggregates under pathological conditions
. Its exact physiological role is still being unraveled, but studies suggest it acts as a chaperone for SNARE proteins and influences dopamine neurotransmission, highlighting its importance in neuron-to-neuron communication
.
However, α-synuclein is infamously known for its misbehavior in Parkinson’s disease (PD). Misfolded α-synuclein can aggregate into fibrils and clump together inside neurons to form Lewy bodies and Lewy neurites (abnormal protein deposits in cell bodies and processes). Lewy bodies containing aggregated α-synuclein are a pathological hallmark of PD and related disorders
. In fact, the first genetic clue linking α-synuclein to PD came in 1997, when a mutation in the SNCA gene (which encodes α-syn) was found in familial PD; soon after, α-synuclein was identified as the major component of Lewy body inclusions in sporadic PD
. This firmly established that when α-synuclein misfolds and accumulates, it is intimately involved in PD pathology.
Lewy bodies (brown round inclusions) and Lewy neurites (thread-like brown structures) in brain tissue, revealed by α-synuclein immunostaining. These protein aggregates consist of misfolded α-synuclein and are a hallmark of Parkinson’s disease pathology
.
The accumulation of α-synuclein aggregates in the brains of people with PD is believed to trigger neuronal dysfunction and death. Research indicates that small soluble aggregates (oligomers or protofibrils) of α-synuclein are particularly toxic, disrupting cellular homeostasis and damaging vital processes
. These toxic α-syn oligomers can impair synaptic function, overload the protein clearance (proteasomal and lysosomal) systems, and harm mitochondria, ultimately leading to the degeneration of dopamine-producing neurons in the substantia nigra
. Moreover, α-synuclein pathology appears to spread in a “prion-like” fashion. Misfolded α-syn can be released from a neuron and taken up by neighboring cells, where it seeds the misfolding of normal α-synuclein
. Over time, this cell-to-cell propagation may explain how PD pathology progresses through the brain in characteristic stages (as described by Braak’s staging hypothesis). In summary, while normal α-synuclein supports synaptic communication, its misfolding and aggregation set off a cascade of neurotoxic events — from Lewy body formation to network-wide spread of protein aggregates — that are central to Parkinson’s disease.
2. Blocking Alpha-Synuclein Aggregation: Can It Slow or Halt Parkinson’s?
Given α-synuclein’s central role in PD pathology, scientists have intensively investigated whether stopping it from misfolding and aggregating could slow or stop the disease’s progression. The prevailing scientific view is that α-synuclein is a priority therapeutic target — in theory, if you prevent its toxic aggregation or remove existing aggregates, you could protect neurons and modify the disease course
. This hypothesis is analogous to targeting beta-amyloid plaques in Alzheimer’s; despite initial setbacks in that field, persistence eventually yielded therapies that clear amyloid and modestly slow cognitive decline
. Similarly in PD, most experts maintain that curbing α-synuclein pathology remains one of the most promising strategies for a disease-modifying therapy
. However, it is also recognized that PD is complex and multifactorial, so while anti-α-syn strategies are logical, they must be rigorously tested. So far, no treatment has definitively proven it can halt PD, but the field has made substantial progress and gleaned critical lessons from ongoing trials
.
Current and emerging approaches to target α-synuclein aggregation include:
- Passive Immunotherapy (Antibodies): Several monoclonal antibodies targeting α-synuclein are in clinical trials. The idea is that antibodies bind to extracellular α-syn aggregates or seeds, marking them for clearance and preventing them from spreading to new cells
- pharmrev.aspetjournals.org
-
- pharmrev.aspetjournals.org
- . One prominent example is prasinezumab, an antibody that binds aggregated α-syn. In a Phase 2 trial (PASADENA), prasinezumab did not significantly improve the primary endpoints, but it showed hints of slowing PD motor progression and was safe and well-tolerated
- michaeljfox.org
- . A subsequent extension study (PADOVA) over 18 months indicated a potential benefit on multiple clinical measures, and an open-label follow-up suggested a trend toward slower symptom progression in treated patients
- michaeljfox.org
- . While results are not yet conclusive, Roche (the trial sponsor) has been encouraged enough to continue analyzing and perhaps pursue further studies. Another antibody, cinpanemab (BIIB054), which targets a different epitope of α-syn, was tested by Biogen. It reached Phase 2, but unfortunately this trial “missed its primary and secondary endpoints” and was discontinued
- pharmrev.aspetjournals.org
- . Despite that setback, these trials confirmed that antibodies can engage the target (for instance, prasinezumab dramatically lowered free α-syn in blood and showed some CSF target engagement) and provided vital data on safety
- pharmrev.aspetjournals.org
-
- pharmrev.aspetjournals.org
- . Researchers are already learning from these results to design stronger next-generation immunotherapies
- michaeljfox.org
-
- michaeljfox.org
- . Notably, passive immunotherapy has precedent in other diseases (e.g. monoclonal antibodies for Alzheimer’s), so many in the PD field remain hopeful that with refined antibodies, optimal dosing, and perhaps earlier intervention, this approach could yield a disease-slowing therapy in the future
- michaeljfox.org
-
- michaeljfox.org
- .
- Active Immunotherapy (Vaccines): Instead of infusing antibodies, active vaccines aim to provoke the patient’s own immune system to produce antibodies against α-synuclein. Several vaccine formulations have been tested in early-stage trials — for example, AFFiRiS’s AFFITOPE PD01A/PD03A (short synthetic peptides mimicking parts of α-syn) and UB312. The goal is to generate long-lasting antibody responses that bind aggregated α-syn and promote its clearance
- pharmrev.aspetjournals.org
- . So far, trials have shown that these vaccines can be safe and elicit antibodies, but it remains to be seen if they significantly alter disease progression. Active immunotherapy could be more cost-effective long-term than monoclonal antibodies, but it must strike a balance in the immune response (to avoid excessive inflammation). These programs are still in Phase 1 or 2, and researchers are monitoring their outcomes closely as another avenue to block α-syn propagation.
- Small-Molecule Inhibitors of Aggregation: Another strategy is to use drugs that directly prevent α-synuclein from misfolding or that break up oligomers. In principle, such a pill could enter the brain and keep α-synuclein in its benign soluble form. One example, from a recent trial, is UCB0599 (minzasolmin) — an orally available compound designed to inhibit α-synuclein from aggregating. In the Phase 2 ORCHESTRA study, UCB0599 was found to be safe and did reach the brain, but after 18 months it showed “no effect on Parkinson’s” progression as measured by clinical scores
- michaeljfox.org
- . Consequently, that program was halted. While disappointing, this result provides important data on dosing and trial design. Other small molecules are in earlier development; notably, anle138b is a promising compound that binds to α-synuclein oligomers. In animal models of synucleinopathy, anle138b reduced oligomer toxicity and improved motor function
- thelancet.com
- . A Phase 1 trial in healthy volunteers showed anle138b achieves brain levels above those needed for efficacy in mice, with a good safety profile
- thelancet.com
-
- thelancet.com
- . This drug (now also called emrusolmin) is moving into patient trials, and researchers are hopeful it could slow disease by stabilizing α-synuclein in a non-toxic form. Beyond these, there are ongoing high-throughput screening efforts to find new small molecules or even natural products that inhibit α-synuclein fibril formation
- mayo.edu
-
- scienceofparkinsons.com
- . For instance, one screen of 2,320 FDA-approved drugs identified a few candidates (like sulfamerazine and tamoxifen) that surprisingly reduced α-syn aggregation in models, though such repurposed hits would need further validation
- scienceofparkinsons.com
- .
- Reducing α-Synuclein Production: Lowering the total amount of α-synuclein in the brain might prevent aggregation simply by reducing the substrate available. Approaches here include antisense oligonucleotides (ASOs) or RNA interference that suppress SNCA gene expression, as well as small molecules that modulate gene regulation. An ASO therapy (ION-464) is in early clinical testing for PD, aiming to bind SNCA mRNA and prevent α-synuclein synthesis
- neurologylive.com
- . Preclinical studies of ASOs in rodent models showed reduced α-syn levels and fewer aggregates, suggesting this approach can mitigate pathology
- pharmrev.aspetjournals.org
- . The challenge is delivering these genetic therapies safely into the brain and avoiding off-target effects (since α-synuclein has normal functions). Another production-targeting approach is testing certain drugs that were observed to lower α-syn expression indirectly — for example, β2-adrenoreceptor agonists like salbutamol were found to reduce SNCA transcription in laboratory studies
- pharmrev.aspetjournals.org
-
- pharmrev.aspetjournals.org
- (interesting epidemiological data also linked salbutamol use to lower PD risk). While not a direct “anti-aggregation” method, lowering α-syn levels could feasibly slow the buildup of toxic aggregates over time. These strategies are still in experimental stages, but they add another angle to cutting down the “seeds” that drive PD.
- Enhancing Aggregate Clearance: Cells have built-in clearance systems (like autophagy and proteasomes) to dispose of misfolded proteins, and boosting these systems might help remove α-synuclein aggregates. Though not targeting aggregation per se, this approach intersects with the goal of reducing toxic α-syn. Drugs like ambroxol (which enhances lysosomal function by boosting the enzyme GCase) are being tested in PD, particularly for patients with GBA mutations, to see if they can speed up the clearance of α-syn and other substrates. Other compounds aim to activate autophagy more directly or upregulate molecular chaperones that can refold or degrade α-syn. For example, inhibitors of prolyl oligopeptidase (PREP) have shown promise in preclinical models — inhibiting PREP was reported to reduce α-syn aggregation and improve cell survival in some studies
- scienceofparkinsons.com
- . While these are adjunct strategies, in combination with direct aggregation blockers they could synergistically keep α-syn levels in check.
Overall, the pipeline of α-synuclein-targeted therapies is diverse and very active. As of late 2024, around 15 different drugs aimed at α-synuclein (by various mechanisms) were in clinical trials
. The consensus in the scientific community is that it’s too early to declare victory or defeat for this approach. The mixed trial results so far are seen not as a reason to abandon the strategy, but as an opportunity to refine it
. Experts point out that neuroprotective therapies often take multiple iterations to get right — for example, initial immunotherapies for Alzheimer’s failed, but ultimately led to effective antibodies when researchers learned from each attempt
. Likewise in PD, each α-syn trial (even those that didn’t meet endpoints) provides crucial data on safety, dosing, and trial design. This knowledge is guiding next-generation approaches: for instance, ensuring drugs reach the brain in sufficient quantity, treating patients earlier in their disease course, and using biomarkers to select patients who actually have underlying α-syn pathology
. In summary, blocking α-synuclein aggregation remains a compelling therapeutic hypothesis for slowing Parkinson’s disease. While not yet proven in practice, the prevailing view is that α-synuclein is still “a key role in the biology of Parkinson’s and should continue to be a focus for therapeutic development”
. Ongoing and future trials will tell how much impact this strategy can have, but there is sustained optimism that taming α-synuclein could alter the course of PD if done effectively.
3. New Genetic Insight: FAM171A2 and Alpha-Synuclein Aggregation (Science, Feb 2025)
A breakthrough study published in Science on Feb 20, 2025 has shed new light on how α-synuclein aggregates spread in the brain, by identifying a specific gene that facilitates this process
. In this study, Wu et al. discovered that a neuronal protein called FAM171A2 acts as a receptor for misfolded α-synuclein fibrils, essentially “rolling out the red carpet” for these toxic aggregates to enter cells
. FAM171A2 was flagged by previous genetic studies (GWAS) as a risk factor for PD, but its function was not well understood
. The new research showed that FAM171A2 on the surface of neurons can directly bind to extracellular α-synuclein fibrils (specifically attaching to the fibril’s C-terminus) and mediate their uptake via endocytosis
. In laboratory models, neurons with higher levels of FAM171A2 gobbled up more α-syn fibrils and subsequently developed more intracellular aggregates and damage. Conversely, knocking down or deleting FAM171A2 made neurons less susceptible to taking up α-syn seeds, which in turn slowed the spread of pathology and protected those cells
. In essence, FAM171A2 functions as a key “gateway” for the cell-to-cell transmission of α-synuclein pathology in Parkinson’s disease.
Why is this discovery important? It provides a concrete biological mechanism linking a PD risk gene to disease progression. The study started from human genetics — finding several variants in the FAM171A2 gene that modestly increase PD risk — and then followed the trail to molecular and animal experiments that explain that risk
. An independent expert, Dr. Michael Henderson, praised the work as a “comprehensive study”, noting how it spanned from human data to mouse models to firmly connect FAM171A2 to α-synuclein pathology
. This kind of full-circle validation strengthens confidence that FAM171A2 is not just a bystander correlation from genetics, but a real player in Parkinson’s disease biology.
From a pathology standpoint, the findings reinforce the concept that Parkinson’s involves a prion-like spread of α-synuclein. They identify FAM171A2 as the likely neuronal receptor that misfolded α-synuclein “hijacks” to propagate itself. This is somewhat analogous to how viruses use specific receptors to invade cells. With FAM171A2, we now know one of the receptors that α-syn aggregates bind to when they move from one neuron to the next
. The study showed that FAM171A2 tends to be enriched in certain brain regions and even found higher FAM171A2 protein levels in the cerebrospinal fluid of patients with PD, hinting that its activity might be upregulated during disease
. All of this converges on a picture in which FAM171A2 accelerates the dissemination of toxic α-syn seeds through the brain’s neural networks, potentially worsening and spreading the neurodegeneration.
Crucially, the Science paper didn’t stop at identifying the problem — it also pointed toward a possible solution. The researchers performed an in silico drug screen and identified an existing drug, bemcentinib, that can block the interaction between α-synuclein fibrils and FAM171A2
. Bemcentinib (also known as BGB324) is a cancer drug (an AXL kinase inhibitor) that, serendipitously, was found to bind to FAM171A2 and inhibit α-synuclein from latching onto it. In cellular experiments and in mouse models of Parkinson’s-like pathology, bemcentinib treatment reduced the uptake of α-syn fibrils by neurons and significantly slowed the spread of α-synuclein aggregates and neurodegeneration
. Essentially, it “barred α-synuclein’s entry” into cells by occupying the FAM171A2 gateway
. This is an exciting proof-of-concept for a new therapeutic strategy: if you can drug the receptor that enables prion-like transmission, you might contain the disease. The authors noted that FAM171A2 is a promising “therapeutic target” for PD, given these results
.
Expert interpretations: The discovery of FAM171A2’s role has been met with optimism in the neuroscience community. It addresses a longstanding question of how α-synuclein travels between cells. By pinning down a specific mediator, it opens up a novel target that researchers can aim at. Dr. Henderson and others emphasized how this finding links genetic risk to a tangible mechanism, which is the kind of insight needed to develop targeted treatments
. It’s also significant that an already-approved drug can influence this mechanism — that accelerates the path toward clinical testing. Of course, experts caution that there’s a lot to do before this translates to patients. We need to confirm these results in further animal studies, understand any side effects of long-term FAM171A2 inhibition, and determine whether bemcentinib (or similar compounds) truly slow neurodegeneration in PD models. But as a commentary in AlzForum summed up, this study provides a “newly identified receptor” that fast-tracks α-syn spread and a potential way to block it
. It’s a prime example of how cutting-edge research can yield both fundamental knowledge and a therapeutic lead. In the short term, the FAM171A2 finding gives researchers a strong rationale to pursue drugs that block α-synuclein cell entry. In the longer term, it enriches our understanding of PD’s molecular underpinnings — knowledge that will inform the design of future therapies.
4. Future Directions: Drug Development and Clinical Trials (Beyond Gene Therapy)
With the role of α-synuclein in PD firmly established and new insights like the FAM171A2 discovery, the next steps in research are focused on translating these findings into effective treatments. Rather than gene therapy (which would involve directly editing or inserting genes, a strategy that faces technical hurdles for disorders like PD), most current efforts emphasize developing drugs or biologics that patients can take to modify the disease course. Below are some key next steps and directions in the field:
- Repurposing and Testing of FAM171A2-Blocking Drugs: A high priority will be to follow up on the Science study by moving bemcentinib (or related compounds) into Parkinson’s models and eventually clinical trials. Since bemcentinib is already approved for cancer and known to be relatively safe in humans, researchers can attempt off-label or clinical pilot studies in PD to see if it impacts α-synuclein pathology (for example, by measuring biomarkers of neuron damage or α-synuclein levels in CSF). Before a full PD trial, additional preclinical work will likely confirm that bemcentinib truly engages FAM171A2 in the brain and doesn’t have unknown toxicity when used chronically. If those boxes are checked, we could envision a Phase 1/2 trial in PD patients (perhaps those in early stages) to evaluate safety and look for signs of slowing disease (maybe through brain imaging or fluid biomarkers). Moreover, drug developers might screen for other FAM171A2 inhibitors or design molecules that are more specific to that receptor. Since FAM171A2 was shown to mediate α-syn uptake, blocking it could essentially “lock the door” on the prion-like spread — a novel disease-modifying approach. This line of work represents a shift from targeting α-synuclein itself to targeting host factors that enable its pathology, and it will be an exciting area to watch.
- Advancing α-Synuclein Antibody Trials to Later Stages: On the immunotherapy front, the mixed results from Phase 2 trials will be used to refine strategies for Phase 3. Roche and its partners are likely parsing the data from prasinezumab’s studies to decide on an optimal trial design moving forward. One consideration is identifying which subgroup of patients may have benefited (e.g. those with faster progression, or certain baseline biomarker profiles) and focusing on them. There is also interest in combining passive immunotherapy with other treatments (for example, co-administering a therapy that increases blood-brain barrier permeability or reduces inflammation, to see if that enhances antibody efficacy). If the hints of motor slowing with prasinezumab are credible, we might see a larger, longer Phase 3 trial in early PD to definitively test if it can delay disability. Additionally, other antibodies are in development — for instance, AstraZeneca/MedImmune’s MEDI1341 (which had strong target engagement in preclinical models
- pharmrev.aspetjournals.org
- ) or newer antibodies optimized to penetrate the brain better. The next few years will likely bring results from ongoing trials (such as a trial of ENT-01, a compound that clears α-syn from the gut to brain, and various vaccine studies). The field is moving toward trials with biomarker endpoints too, not just clinical scales, to directly measure if these drugs are hitting their target (e.g., lowering misfolded α-syn in CSF or slowing the rise of α-syn seed amplification assay signals).
- Incorporating Biomarkers and Early Diagnosis in Trials: A recurring lesson in neurodegenerative disease research is that earlier intervention yields better chances of success. Future PD trials targeting α-synuclein are likely to recruit patients at the earliest stages possible — perhaps even people with prodromal signs (such as REM sleep behavior disorder or genetic risk carriers) who have evidence of α-syn pathology. Thanks to breakthroughs like the α-synuclein seed amplification assay (SAA), we can now detect misfolded α-syn in living patients’ spinal fluid
- michaeljfox.org
- . Trials going forward can use such assays to ensure participants truly have the protein pathology the drug targets (in the past, some trial subjects might not have had classic α-synuclein pathology, diluting the results). Moreover, researchers are striving to develop quantitative biomarkers — imaging agents that bind α-syn aggregates in the brain, or blood tests that reflect the burden of misfolded α-syn
- michaeljfox.org
- . These tools would be game-changing: for example, a PET scan for α-syn could show whether a drug is clearing brain aggregates, much like amyloid scans are used in Alzheimer’s trials
- pharmrev.aspetjournals.org
-
- pharmrev.aspetjournals.org
- . The next steps in research include validating such imaging tracers and refining assays like the SAA so they can track changes over time, not just give a yes/no diagnostic. Improved biomarkers will make clinical trials more efficient (by selecting the right patients and measuring drug impact more directly)
- michaeljfox.org
- . In fact, sponsors are already starting to apply SAA to archived samples from past trials to understand who had pathology and whether that correlated with response
- michaeljfox.org
-
- michaeljfox.org
- . Going forward, expect most disease-modification trials in PD to require biomarker confirmation of α-syn pathology as an entry criterion.
- Exploring Combination Therapies: As PD mechanisms are diverse, a single agent might not be enough to markedly slow the disease. Researchers are considering combination approaches — for instance, pairing an α-synuclein aggregation blocker with a therapy that boosts neuron survival or reduces inflammation. One hypothetical combination could be an α-syn antibody together with a neurotrophic factor (to support neuron health) or with a LRRK2 inhibitor (if the patient also has a LRRK2 mutation affecting lysosomal cleanup). While combination trials are complex, preclinical studies are being done to see if targeting two nodes in the disease process yields additive benefits. In the long run, patients might receive a “cocktail” of disease-modifying drugs (akin to how hypertension or HIV is treated) — for example, one drug to reduce α-syn production, another to prevent its aggregation, and perhaps another to mitigate downstream effects of any aggregates that still form. The field is gradually moving in this direction as more therapeutic candidates become available.
- Continued Development of Small Molecules and Other Novel Therapies: On the small-molecule front, drugs like anle138b will proceed to Phase 2 to test efficacy in patients. If anle138b shows even a modest slowing of progression in a trial, it would validate the approach of targeting oligomers. Other molecules are in various stages: for example, nilotinib (a leukemia drug) has been trialed for PD on the rationale that it enhances autophagic clearance of proteins — results have been mixed, but it spurred interest in drugs that can boost the cell’s garbage disposal of α-syn. Meanwhile, biotech companies are applying cutting-edge methods to discover entirely new classes of α-syn targeting drugs, such as peptidomimetics (small protein-like molecules) that bind α-syn and prevent it from misfolding
- molecularneurodegeneration.biomedcentral.com
- . There’s also work on intrabodies (antibodies that work inside cells) delivered via gene therapy to bind α-syn where it aggregates intracellularly — though gene therapy is not the main focus now, it could become relevant if these intrabodies prove effective in animal models. Importantly, any new drug candidate will go through the pipeline of Phase 1 (safety) and Phase 2 (proof of concept) trials. Thanks to global initiatives and collaborations, there is more support than ever for moving promising lab discoveries into clinical testing for PD.
In all these efforts, the emphasis is on disease modification — slowing or stopping neurodegeneration — rather than just symptom relief. This is a challenging goal, but the PD research community is armed with better tools and knowledge than even a decade ago. The coming years will likely see multiple Phase 2/3 trials read out for drugs targeting α-synuclein or its pathways. If one or more show positive results (even moderate efficacy), it would be a landmark moment, as currently there are “no proven safe and effective treatments to slow down the progression” of PD
. Researchers are cautiously optimistic that by persisting with well-designed trials, using biomarkers to guide them, and learning from each attempt, they will eventually crack the code of disease modification
.
In summary, the next steps in Parkinson’s research revolve around translational science — taking discoveries like the alpha-synuclein–FAM171A2 interaction and turning them into therapies that can be tested in patients. Rather than altering genes directly in patients, the focus is on drugs (small molecules, antibodies, antisense, etc.) that can interfere with the pathogenic processes genes control. This includes advancing compounds that block α-synuclein aggregation or spread, optimizing immunotherapies, and employing biomarkers to pick the right patients and endpoints. It’s an iterative process: each trial, whether it succeeds or “fails,” adds to our understanding and informs the next generation of interventions
. The field is steadily moving toward the goal of altering Parkinson’s disease progression. While challenges remain — such as the variability of the disease and the blood-brain barrier limiting some treatments — the concerted efforts in drug development and clinical research give hope that therapies targeting alpha-synuclein (and related mechanisms) can deliver meaningful benefits for patients in the not-too-distant future. The convergence of biological insights (like the new gene discovery) with innovative therapeutics and improved clinical trial methods paints an encouraging picture of the road ahead in the fight against Parkinson’s.
Sources: The role of α-synuclein in PD pathology
; therapeutic strategies targeting α-synuclein
; recent trial results and expert commentary on α-syn-targeted therapies
; Science 2025 study identifying FAM171A2 as an α-synuclein receptor and therapeutic target
; Alzforum news & expert quote on FAM171A2 findings
; future directions in PD research and the need for biomarkers
Parkinson DiseaseI have been diagnosed in 2020 with Parkinson’s disease. My background is a MSC in Biochemistry and a PhD in Biology. After 10 years in the lab I spent most of my life on data presentation and recovery in the context of the “Semantic Web”. With the developing AI revolution I was obviously excited what this could mean for fighting PD.
I am convinced that (already the existing level) AI can revolutionize medical research development. The problem in research, but especially in biomedical research is that 1000 and 1000nds of research groups work in parallel, without real knowledge exchange. The existing system (conferences and scientific journals, individual exchanges) is not sufficient any more. the sheer amount of data is too bigto be handled by human beeings. there is also a “social” issue. Dealing with data from other, making critical reviews is not the way for young scientists to get a name , it has to be something new from the lab. AI could be one solution. An AI engine could look on ALL of PD together to find common patterns, divergence and upcoming trends.
I ask myself why this does not happen.The problem is again compartimetalization.
A good amount of medical doctors is far away from IT developments. When they ask the health history of a patient, they note it with pensil on paper. On paper are patient reports. There is very little data exchange. well meant, but badly constructed data protection rules do not help.
Scientists have a better relationship to IT, but it is mostly restricted to the use of tools to produce and elaborate their own data. I think very few would be able to use the API of openAI to make a specific interface for their area.
Better is the situation with engineers. The first AI implementations for PD are tools, mostly for early diagnosis.
I initially wanted to step into this void myselve and to develop a system, that applies AI to PD. But I quickly got convinced that I am lacking competence and scale.
But I carry on firing prompts towards my open AI suite. The last result that I got applying “Deep research”, is really remarkable. The development is as follows.
My initial prompt: “I want to know everything about the role o f alfa synuclein in the developoment of Parkinsons disease. Is there a common view that blocking agglomeration of alfa synuclein stops the disease? What is the importance aboutthe research published in Science in february 25, identifying a gene that is responsible for the agglomeration of alfa synuclein. What should be the nextsteps in the research?”
the AI answered:”I can certainly gather comprehensive information on alpha-synuclein’s role in Parkinson’s disease, the impact of blocking its aggregation, and the significance of the February 25th Science publication on a gene linked to its aggregation. To ensure I provide the most relevant details, could you clarify:
- Are you interested in a general overview of alpha-synuclein’s role or a deep dive into specific mechanisms?
- Should I focus on therapeutic approaches currently under research, including the feasibility of stopping the disease by blocking aggregation?
- Would you like an analysis of the February 25th Science paper’s findings, its implications, and expert opinions on it?
- Should I include perspectives on the next steps in research, including drug development, gene therapy, or clinical trials?
Let me know how detailed and technical you’d like the information to be!”
Me: “first question: general overview, second question: yes focus on therapeutic approaches is importatn, thirs question: yes! 4th question: yes, especially drug development and chemical trials. less gene therapy. Over all: detailed, yes , but understandable also for scientific skilled lay person”
theAI:”Got it! I will provide a detailed but understandable overview of alpha-synuclein’s role in Parkinson’s disease, focusing on:
- The general mechanisms and significance of alpha-synuclein in disease progression.
- The potential of blocking its aggregation as a therapeutic strategy, including existing and emerging treatments.
- An analysis of the February 25th Science paper, its findings, and expert interpretations.
- The next steps in research, with a strong focus on drug development and clinical trials rather than gene therapy.
I will get back to you with a comprehensive report soon!”
After half an hour I got the following piece:
Alpha-Synuclein in Parkinson’s Disease: Role, Therapeutic Targeting, and Recent Advances
1. Biological Function of Alpha-Synuclein and Parkinson’s Pathology
Alpha-synuclein (α-syn) is a small, soluble protein abundantly expressed in neurons, especially at presynaptic terminals. Under normal conditions, it helps regulate synaptic function — for example, it binds to synaptic vesicles and assists in neurotransmitter release and vesicle recycling
. α-Synuclein is natively unstructured in solution but can adopt an α-helical shape when bound to lipid membranes (such as vesicles) or form β-sheet-rich aggregates under pathological conditions
. Its exact physiological role is still being unraveled, but studies suggest it acts as a chaperone for SNARE proteins and influences dopamine neurotransmission, highlighting its importance in neuron-to-neuron communication
.
However, α-synuclein is infamously known for its misbehavior in Parkinson’s disease (PD). Misfolded α-synuclein can aggregate into fibrils and clump together inside neurons to form Lewy bodies and Lewy neurites (abnormal protein deposits in cell bodies and processes). Lewy bodies containing aggregated α-synuclein are a pathological hallmark of PD and related disorders
. In fact, the first genetic clue linking α-synuclein to PD came in 1997, when a mutation in the SNCA gene (which encodes α-syn) was found in familial PD; soon after, α-synuclein was identified as the major component of Lewy body inclusions in sporadic PD
. This firmly established that when α-synuclein misfolds and accumulates, it is intimately involved in PD pathology.
Lewy bodies (brown round inclusions) and Lewy neurites (thread-like brown structures) in brain tissue, revealed by α-synuclein immunostaining. These protein aggregates consist of misfolded α-synuclein and are a hallmark of Parkinson’s disease pathology
.
The accumulation of α-synuclein aggregates in the brains of people with PD is believed to trigger neuronal dysfunction and death. Research indicates that small soluble aggregates (oligomers or protofibrils) of α-synuclein are particularly toxic, disrupting cellular homeostasis and damaging vital processes
. These toxic α-syn oligomers can impair synaptic function, overload the protein clearance (proteasomal and lysosomal) systems, and harm mitochondria, ultimately leading to the degeneration of dopamine-producing neurons in the substantia nigra
. Moreover, α-synuclein pathology appears to spread in a “prion-like” fashion. Misfolded α-syn can be released from a neuron and taken up by neighboring cells, where it seeds the misfolding of normal α-synuclein
. Over time, this cell-to-cell propagation may explain how PD pathology progresses through the brain in characteristic stages (as described by Braak’s staging hypothesis). In summary, while normal α-synuclein supports synaptic communication, its misfolding and aggregation set off a cascade of neurotoxic events — from Lewy body formation to network-wide spread of protein aggregates — that are central to Parkinson’s disease.
2. Blocking Alpha-Synuclein Aggregation: Can It Slow or Halt Parkinson’s?
Given α-synuclein’s central role in PD pathology, scientists have intensively investigated whether stopping it from misfolding and aggregating could slow or stop the disease’s progression. The prevailing scientific view is that α-synuclein is a priority therapeutic target — in theory, if you prevent its toxic aggregation or remove existing aggregates, you could protect neurons and modify the disease course
. This hypothesis is analogous to targeting beta-amyloid plaques in Alzheimer’s; despite initial setbacks in that field, persistence eventually yielded therapies that clear amyloid and modestly slow cognitive decline
. Similarly in PD, most experts maintain that curbing α-synuclein pathology remains one of the most promising strategies for a disease-modifying therapy
. However, it is also recognized that PD is complex and multifactorial, so while anti-α-syn strategies are logical, they must be rigorously tested. So far, no treatment has definitively proven it can halt PD, but the field has made substantial progress and gleaned critical lessons from ongoing trials
.
Current and emerging approaches to target α-synuclein aggregation include:
- Passive Immunotherapy (Antibodies): Several monoclonal antibodies targeting α-synuclein are in clinical trials. The idea is that antibodies bind to extracellular α-syn aggregates or seeds, marking them for clearance and preventing them from spreading to new cells
- pharmrev.aspetjournals.org
-
- pharmrev.aspetjournals.org
- . One prominent example is prasinezumab, an antibody that binds aggregated α-syn. In a Phase 2 trial (PASADENA), prasinezumab did not significantly improve the primary endpoints, but it showed hints of slowing PD motor progression and was safe and well-tolerated
- michaeljfox.org
- . A subsequent extension study (PADOVA) over 18 months indicated a potential benefit on multiple clinical measures, and an open-label follow-up suggested a trend toward slower symptom progression in treated patients
- michaeljfox.org
- . While results are not yet conclusive, Roche (the trial sponsor) has been encouraged enough to continue analyzing and perhaps pursue further studies. Another antibody, cinpanemab (BIIB054), which targets a different epitope of α-syn, was tested by Biogen. It reached Phase 2, but unfortunately this trial “missed its primary and secondary endpoints” and was discontinued
- pharmrev.aspetjournals.org
- . Despite that setback, these trials confirmed that antibodies can engage the target (for instance, prasinezumab dramatically lowered free α-syn in blood and showed some CSF target engagement) and provided vital data on safety
- pharmrev.aspetjournals.org
-
- pharmrev.aspetjournals.org
- . Researchers are already learning from these results to design stronger next-generation immunotherapies
- michaeljfox.org
-
- michaeljfox.org
- . Notably, passive immunotherapy has precedent in other diseases (e.g. monoclonal antibodies for Alzheimer’s), so many in the PD field remain hopeful that with refined antibodies, optimal dosing, and perhaps earlier intervention, this approach could yield a disease-slowing therapy in the future
- michaeljfox.org
-
- michaeljfox.org
- .
- Active Immunotherapy (Vaccines): Instead of infusing antibodies, active vaccines aim to provoke the patient’s own immune system to produce antibodies against α-synuclein. Several vaccine formulations have been tested in early-stage trials — for example, AFFiRiS’s AFFITOPE PD01A/PD03A (short synthetic peptides mimicking parts of α-syn) and UB312. The goal is to generate long-lasting antibody responses that bind aggregated α-syn and promote its clearance
- pharmrev.aspetjournals.org
- . So far, trials have shown that these vaccines can be safe and elicit antibodies, but it remains to be seen if they significantly alter disease progression. Active immunotherapy could be more cost-effective long-term than monoclonal antibodies, but it must strike a balance in the immune response (to avoid excessive inflammation). These programs are still in Phase 1 or 2, and researchers are monitoring their outcomes closely as another avenue to block α-syn propagation.
- Small-Molecule Inhibitors of Aggregation: Another strategy is to use drugs that directly prevent α-synuclein from misfolding or that break up oligomers. In principle, such a pill could enter the brain and keep α-synuclein in its benign soluble form. One example, from a recent trial, is UCB0599 (minzasolmin) — an orally available compound designed to inhibit α-synuclein from aggregating. In the Phase 2 ORCHESTRA study, UCB0599 was found to be safe and did reach the brain, but after 18 months it showed “no effect on Parkinson’s” progression as measured by clinical scores
- michaeljfox.org
- . Consequently, that program was halted. While disappointing, this result provides important data on dosing and trial design. Other small molecules are in earlier development; notably, anle138b is a promising compound that binds to α-synuclein oligomers. In animal models of synucleinopathy, anle138b reduced oligomer toxicity and improved motor function
- thelancet.com
- . A Phase 1 trial in healthy volunteers showed anle138b achieves brain levels above those needed for efficacy in mice, with a good safety profile
- thelancet.com
-
- thelancet.com
- . This drug (now also called emrusolmin) is moving into patient trials, and researchers are hopeful it could slow disease by stabilizing α-synuclein in a non-toxic form. Beyond these, there are ongoing high-throughput screening efforts to find new small molecules or even natural products that inhibit α-synuclein fibril formation
- mayo.edu
-
- scienceofparkinsons.com
- . For instance, one screen of 2,320 FDA-approved drugs identified a few candidates (like sulfamerazine and tamoxifen) that surprisingly reduced α-syn aggregation in models, though such repurposed hits would need further validation
- scienceofparkinsons.com
- .
- Reducing α-Synuclein Production: Lowering the total amount of α-synuclein in the brain might prevent aggregation simply by reducing the substrate available. Approaches here include antisense oligonucleotides (ASOs) or RNA interference that suppress SNCA gene expression, as well as small molecules that modulate gene regulation. An ASO therapy (ION-464) is in early clinical testing for PD, aiming to bind SNCA mRNA and prevent α-synuclein synthesis
- neurologylive.com
- . Preclinical studies of ASOs in rodent models showed reduced α-syn levels and fewer aggregates, suggesting this approach can mitigate pathology
- pharmrev.aspetjournals.org
- . The challenge is delivering these genetic therapies safely into the brain and avoiding off-target effects (since α-synuclein has normal functions). Another production-targeting approach is testing certain drugs that were observed to lower α-syn expression indirectly — for example, β2-adrenoreceptor agonists like salbutamol were found to reduce SNCA transcription in laboratory studies
- pharmrev.aspetjournals.org
-
- pharmrev.aspetjournals.org
- (interesting epidemiological data also linked salbutamol use to lower PD risk). While not a direct “anti-aggregation” method, lowering α-syn levels could feasibly slow the buildup of toxic aggregates over time. These strategies are still in experimental stages, but they add another angle to cutting down the “seeds” that drive PD.
- Enhancing Aggregate Clearance: Cells have built-in clearance systems (like autophagy and proteasomes) to dispose of misfolded proteins, and boosting these systems might help remove α-synuclein aggregates. Though not targeting aggregation per se, this approach intersects with the goal of reducing toxic α-syn. Drugs like ambroxol (which enhances lysosomal function by boosting the enzyme GCase) are being tested in PD, particularly for patients with GBA mutations, to see if they can speed up the clearance of α-syn and other substrates. Other compounds aim to activate autophagy more directly or upregulate molecular chaperones that can refold or degrade α-syn. For example, inhibitors of prolyl oligopeptidase (PREP) have shown promise in preclinical models — inhibiting PREP was reported to reduce α-syn aggregation and improve cell survival in some studies
- scienceofparkinsons.com
- . While these are adjunct strategies, in combination with direct aggregation blockers they could synergistically keep α-syn levels in check.
Overall, the pipeline of α-synuclein-targeted therapies is diverse and very active. As of late 2024, around 15 different drugs aimed at α-synuclein (by various mechanisms) were in clinical trials
. The consensus in the scientific community is that it’s too early to declare victory or defeat for this approach. The mixed trial results so far are seen not as a reason to abandon the strategy, but as an opportunity to refine it
. Experts point out that neuroprotective therapies often take multiple iterations to get right — for example, initial immunotherapies for Alzheimer’s failed, but ultimately led to effective antibodies when researchers learned from each attempt
. Likewise in PD, each α-syn trial (even those that didn’t meet endpoints) provides crucial data on safety, dosing, and trial design. This knowledge is guiding next-generation approaches: for instance, ensuring drugs reach the brain in sufficient quantity, treating patients earlier in their disease course, and using biomarkers to select patients who actually have underlying α-syn pathology
. In summary, blocking α-synuclein aggregation remains a compelling therapeutic hypothesis for slowing Parkinson’s disease. While not yet proven in practice, the prevailing view is that α-synuclein is still “a key role in the biology of Parkinson’s and should continue to be a focus for therapeutic development”
. Ongoing and future trials will tell how much impact this strategy can have, but there is sustained optimism that taming α-synuclein could alter the course of PD if done effectively.
3. New Genetic Insight: FAM171A2 and Alpha-Synuclein Aggregation (Science, Feb 2025)
A breakthrough study published in Science on Feb 20, 2025 has shed new light on how α-synuclein aggregates spread in the brain, by identifying a specific gene that facilitates this process
. In this study, Wu et al. discovered that a neuronal protein called FAM171A2 acts as a receptor for misfolded α-synuclein fibrils, essentially “rolling out the red carpet” for these toxic aggregates to enter cells
. FAM171A2 was flagged by previous genetic studies (GWAS) as a risk factor for PD, but its function was not well understood
. The new research showed that FAM171A2 on the surface of neurons can directly bind to extracellular α-synuclein fibrils (specifically attaching to the fibril’s C-terminus) and mediate their uptake via endocytosis
. In laboratory models, neurons with higher levels of FAM171A2 gobbled up more α-syn fibrils and subsequently developed more intracellular aggregates and damage. Conversely, knocking down or deleting FAM171A2 made neurons less susceptible to taking up α-syn seeds, which in turn slowed the spread of pathology and protected those cells
. In essence, FAM171A2 functions as a key “gateway” for the cell-to-cell transmission of α-synuclein pathology in Parkinson’s disease.
Why is this discovery important? It provides a concrete biological mechanism linking a PD risk gene to disease progression. The study started from human genetics — finding several variants in the FAM171A2 gene that modestly increase PD risk — and then followed the trail to molecular and animal experiments that explain that risk
. An independent expert, Dr. Michael Henderson, praised the work as a “comprehensive study”, noting how it spanned from human data to mouse models to firmly connect FAM171A2 to α-synuclein pathology
. This kind of full-circle validation strengthens confidence that FAM171A2 is not just a bystander correlation from genetics, but a real player in Parkinson’s disease biology.
From a pathology standpoint, the findings reinforce the concept that Parkinson’s involves a prion-like spread of α-synuclein. They identify FAM171A2 as the likely neuronal receptor that misfolded α-synuclein “hijacks” to propagate itself. This is somewhat analogous to how viruses use specific receptors to invade cells. With FAM171A2, we now know one of the receptors that α-syn aggregates bind to when they move from one neuron to the next
. The study showed that FAM171A2 tends to be enriched in certain brain regions and even found higher FAM171A2 protein levels in the cerebrospinal fluid of patients with PD, hinting that its activity might be upregulated during disease
. All of this converges on a picture in which FAM171A2 accelerates the dissemination of toxic α-syn seeds through the brain’s neural networks, potentially worsening and spreading the neurodegeneration.
Crucially, the Science paper didn’t stop at identifying the problem — it also pointed toward a possible solution. The researchers performed an in silico drug screen and identified an existing drug, bemcentinib, that can block the interaction between α-synuclein fibrils and FAM171A2
. Bemcentinib (also known as BGB324) is a cancer drug (an AXL kinase inhibitor) that, serendipitously, was found to bind to FAM171A2 and inhibit α-synuclein from latching onto it. In cellular experiments and in mouse models of Parkinson’s-like pathology, bemcentinib treatment reduced the uptake of α-syn fibrils by neurons and significantly slowed the spread of α-synuclein aggregates and neurodegeneration
. Essentially, it “barred α-synuclein’s entry” into cells by occupying the FAM171A2 gateway
. This is an exciting proof-of-concept for a new therapeutic strategy: if you can drug the receptor that enables prion-like transmission, you might contain the disease. The authors noted that FAM171A2 is a promising “therapeutic target” for PD, given these results
.
Expert interpretations: The discovery of FAM171A2’s role has been met with optimism in the neuroscience community. It addresses a longstanding question of how α-synuclein travels between cells. By pinning down a specific mediator, it opens up a novel target that researchers can aim at. Dr. Henderson and others emphasized how this finding links genetic risk to a tangible mechanism, which is the kind of insight needed to develop targeted treatments
. It’s also significant that an already-approved drug can influence this mechanism — that accelerates the path toward clinical testing. Of course, experts caution that there’s a lot to do before this translates to patients. We need to confirm these results in further animal studies, understand any side effects of long-term FAM171A2 inhibition, and determine whether bemcentinib (or similar compounds) truly slow neurodegeneration in PD models. But as a commentary in AlzForum summed up, this study provides a “newly identified receptor” that fast-tracks α-syn spread and a potential way to block it
. It’s a prime example of how cutting-edge research can yield both fundamental knowledge and a therapeutic lead. In the short term, the FAM171A2 finding gives researchers a strong rationale to pursue drugs that block α-synuclein cell entry. In the longer term, it enriches our understanding of PD’s molecular underpinnings — knowledge that will inform the design of future therapies.
4. Future Directions: Drug Development and Clinical Trials (Beyond Gene Therapy)
With the role of α-synuclein in PD firmly established and new insights like the FAM171A2 discovery, the next steps in research are focused on translating these findings into effective treatments. Rather than gene therapy (which would involve directly editing or inserting genes, a strategy that faces technical hurdles for disorders like PD), most current efforts emphasize developing drugs or biologics that patients can take to modify the disease course. Below are some key next steps and directions in the field:
- Repurposing and Testing of FAM171A2-Blocking Drugs: A high priority will be to follow up on the Science study by moving bemcentinib (or related compounds) into Parkinson’s models and eventually clinical trials. Since bemcentinib is already approved for cancer and known to be relatively safe in humans, researchers can attempt off-label or clinical pilot studies in PD to see if it impacts α-synuclein pathology (for example, by measuring biomarkers of neuron damage or α-synuclein levels in CSF). Before a full PD trial, additional preclinical work will likely confirm that bemcentinib truly engages FAM171A2 in the brain and doesn’t have unknown toxicity when used chronically. If those boxes are checked, we could envision a Phase 1/2 trial in PD patients (perhaps those in early stages) to evaluate safety and look for signs of slowing disease (maybe through brain imaging or fluid biomarkers). Moreover, drug developers might screen for other FAM171A2 inhibitors or design molecules that are more specific to that receptor. Since FAM171A2 was shown to mediate α-syn uptake, blocking it could essentially “lock the door” on the prion-like spread — a novel disease-modifying approach. This line of work represents a shift from targeting α-synuclein itself to targeting host factors that enable its pathology, and it will be an exciting area to watch.
- Advancing α-Synuclein Antibody Trials to Later Stages: On the immunotherapy front, the mixed results from Phase 2 trials will be used to refine strategies for Phase 3. Roche and its partners are likely parsing the data from prasinezumab’s studies to decide on an optimal trial design moving forward. One consideration is identifying which subgroup of patients may have benefited (e.g. those with faster progression, or certain baseline biomarker profiles) and focusing on them. There is also interest in combining passive immunotherapy with other treatments (for example, co-administering a therapy that increases blood-brain barrier permeability or reduces inflammation, to see if that enhances antibody efficacy). If the hints of motor slowing with prasinezumab are credible, we might see a larger, longer Phase 3 trial in early PD to definitively test if it can delay disability. Additionally, other antibodies are in development — for instance, AstraZeneca/MedImmune’s MEDI1341 (which had strong target engagement in preclinical models
- pharmrev.aspetjournals.org
- ) or newer antibodies optimized to penetrate the brain better. The next few years will likely bring results from ongoing trials (such as a trial of ENT-01, a compound that clears α-syn from the gut to brain, and various vaccine studies). The field is moving toward trials with biomarker endpoints too, not just clinical scales, to directly measure if these drugs are hitting their target (e.g., lowering misfolded α-syn in CSF or slowing the rise of α-syn seed amplification assay signals).
- Incorporating Biomarkers and Early Diagnosis in Trials: A recurring lesson in neurodegenerative disease research is that earlier intervention yields better chances of success. Future PD trials targeting α-synuclein are likely to recruit patients at the earliest stages possible — perhaps even people with prodromal signs (such as REM sleep behavior disorder or genetic risk carriers) who have evidence of α-syn pathology. Thanks to breakthroughs like the α-synuclein seed amplification assay (SAA), we can now detect misfolded α-syn in living patients’ spinal fluid
- michaeljfox.org
- . Trials going forward can use such assays to ensure participants truly have the protein pathology the drug targets (in the past, some trial subjects might not have had classic α-synuclein pathology, diluting the results). Moreover, researchers are striving to develop quantitative biomarkers — imaging agents that bind α-syn aggregates in the brain, or blood tests that reflect the burden of misfolded α-syn
- michaeljfox.org
- . These tools would be game-changing: for example, a PET scan for α-syn could show whether a drug is clearing brain aggregates, much like amyloid scans are used in Alzheimer’s trials
- pharmrev.aspetjournals.org
-
- pharmrev.aspetjournals.org
- . The next steps in research include validating such imaging tracers and refining assays like the SAA so they can track changes over time, not just give a yes/no diagnostic. Improved biomarkers will make clinical trials more efficient (by selecting the right patients and measuring drug impact more directly)
- michaeljfox.org
- . In fact, sponsors are already starting to apply SAA to archived samples from past trials to understand who had pathology and whether that correlated with response
- michaeljfox.org
-
- michaeljfox.org
- . Going forward, expect most disease-modification trials in PD to require biomarker confirmation of α-syn pathology as an entry criterion.
- Exploring Combination Therapies: As PD mechanisms are diverse, a single agent might not be enough to markedly slow the disease. Researchers are considering combination approaches — for instance, pairing an α-synuclein aggregation blocker with a therapy that boosts neuron survival or reduces inflammation. One hypothetical combination could be an α-syn antibody together with a neurotrophic factor (to support neuron health) or with a LRRK2 inhibitor (if the patient also has a LRRK2 mutation affecting lysosomal cleanup). While combination trials are complex, preclinical studies are being done to see if targeting two nodes in the disease process yields additive benefits. In the long run, patients might receive a “cocktail” of disease-modifying drugs (akin to how hypertension or HIV is treated) — for example, one drug to reduce α-syn production, another to prevent its aggregation, and perhaps another to mitigate downstream effects of any aggregates that still form. The field is gradually moving in this direction as more therapeutic candidates become available.
- Continued Development of Small Molecules and Other Novel Therapies: On the small-molecule front, drugs like anle138b will proceed to Phase 2 to test efficacy in patients. If anle138b shows even a modest slowing of progression in a trial, it would validate the approach of targeting oligomers. Other molecules are in various stages: for example, nilotinib (a leukemia drug) has been trialed for PD on the rationale that it enhances autophagic clearance of proteins — results have been mixed, but it spurred interest in drugs that can boost the cell’s garbage disposal of α-syn. Meanwhile, biotech companies are applying cutting-edge methods to discover entirely new classes of α-syn targeting drugs, such as peptidomimetics (small protein-like molecules) that bind α-syn and prevent it from misfolding
- molecularneurodegeneration.biomedcentral.com
- . There’s also work on intrabodies (antibodies that work inside cells) delivered via gene therapy to bind α-syn where it aggregates intracellularly — though gene therapy is not the main focus now, it could become relevant if these intrabodies prove effective in animal models. Importantly, any new drug candidate will go through the pipeline of Phase 1 (safety) and Phase 2 (proof of concept) trials. Thanks to global initiatives and collaborations, there is more support than ever for moving promising lab discoveries into clinical testing for PD.
In all these efforts, the emphasis is on disease modification — slowing or stopping neurodegeneration — rather than just symptom relief. This is a challenging goal, but the PD research community is armed with better tools and knowledge than even a decade ago. The coming years will likely see multiple Phase 2/3 trials read out for drugs targeting α-synuclein or its pathways. If one or more show positive results (even moderate efficacy), it would be a landmark moment, as currently there are “no proven safe and effective treatments to slow down the progression” of PD
. Researchers are cautiously optimistic that by persisting with well-designed trials, using biomarkers to guide them, and learning from each attempt, they will eventually crack the code of disease modification
.
In summary, the next steps in Parkinson’s research revolve around translational science — taking discoveries like the alpha-synuclein–FAM171A2 interaction and turning them into therapies that can be tested in patients. Rather than altering genes directly in patients, the focus is on drugs (small molecules, antibodies, antisense, etc.) that can interfere with the pathogenic processes genes control. This includes advancing compounds that block α-synuclein aggregation or spread, optimizing immunotherapies, and employing biomarkers to pick the right patients and endpoints. It’s an iterative process: each trial, whether it succeeds or “fails,” adds to our understanding and informs the next generation of interventions
. The field is steadily moving toward the goal of altering Parkinson’s disease progression. While challenges remain — such as the variability of the disease and the blood-brain barrier limiting some treatments — the concerted efforts in drug development and clinical research give hope that therapies targeting alpha-synuclein (and related mechanisms) can deliver meaningful benefits for patients in the not-too-distant future. The convergence of biological insights (like the new gene discovery) with innovative therapeutics and improved clinical trial methods paints an encouraging picture of the road ahead in the fight against Parkinson’s.
Sources: The role of α-synuclein in PD pathology
; therapeutic strategies targeting α-synuclein
; recent trial results and expert commentary on α-syn-targeted therapies
; Science 2025 study identifying FAM171A2 as an α-synuclein receptor and therapeutic target
; Alzforum news & expert quote on FAM171A2 findings
; future directions in PD research and the need for biomarkers