FAM171A2: Urgent need for research

Science Magazine, February 21, 2025, published a paper by Kai-Min Wu and others titled “Neuronal FAM171A2 mediates α-synuclein fibril uptake and drives Parkinson’s disease.” This study proposed that FAM171A2 is a key player in the development of Parkinson’s disease (PD), demonstrating that the protein mediates neuronal uptake of pathogenic α-synuclein fibrils. Notably, the paper introduced an inhibitor targeting FAM171A2, potentially interrupting this uptake mechanism — an intervention that could represent a breakthrough in PD therapy.

Given this potential significance, we conducted a review of the existing literature to assess what is currently known about FAM171A2. A PubMed search yielded only five records on this gene, published between 2018 and 2025. A broader search provided no additional substantive insights. To enhance our understanding, we prompted ChatGPT (OpenAI, March 29 version) with the following request:

“I want a review about: a) known functions of FAM171A2, b) involvement of the gene in pathologies, c) open questions, and d) labs currently working on it.”

a) Known Functions of FAM171A2

FAM171A2 encodes a single-pass transmembrane protein whose physiological function remains poorly understood. According to the Human Protein Atlas, it is predicted to localize to the membrane, and recent data suggests interaction with DYNLL1 (Dynein Light Chain LC8-Type 1), implying a role in intracellular transport mechanisms. Emerging studies indicate that FAM171A2 may act as a neuronal receptor involved in the endocytosis of pathological α-synuclein fibrils. Overexpression of FAM171A2 promotes uptake and propagation of these fibrils, while neuronal knockdown exhibits protective effects.

b) Involvement of FAM171A2 in Pathologies

Variants in FAM171A2 have been associated with increased PD risk, potentially through modulation of α-synuclein aggregation. Additionally, FAM171A2 has been identified as a regulator of progranulin (GRN), a protein implicated in several neurodegenerative conditions, including frontotemporal dementia and Alzheimer’s disease. Alterations in FAM171A2 expression can influence GRN levels, thereby modifying disease risk. FAM171A2 has also been recognized as a prognostic marker in renal cancer.

Footnote on Progranulin: Progranulin is a secreted glycoprotein involved in neuronal survival, lysosomal function, and inflammation modulation. Encoded by the GRN gene, its deficiency or mutation has been linked to frontotemporal lobar degeneration and other neurodegenerative conditions.

c) Open Questions

• What is the precise physiological role of FAM171A2 in neurons?
• By what mechanisms does it mediate α-synuclein fibril uptake and contribute to neurotoxicity?
• Can FAM171A2 be effectively and safely targeted for therapeutic purposes?
• Are there additional disease contexts, beyond PD and renal cancer, in which FAM171A2 is relevant?

d) Laboratories Researching FAM171A2

• Fudan University (China): A group led by Dr. Jin-Tai Yu has been actively investigating FAM171A2 in the context of neurodegeneration, including GWAS studies and mechanistic investigations of α-synuclein pathology.
• KU Leuven (Belgium): Researchers are studying FAM171A2’s potential role as a synaptic adhesion molecule and its links to dendritic morphology and psychiatric disorders.

These findings reflect the growing but still limited exploration of FAM171A2 in neuroscience, and they underscore the urgent need for further research.

Selected Bibliography

1. “The FAM171A2 gene is a key regulator of progranulin expression and modifies the risk of multiple neurodegenerative diseases.”
   Authors: Wei Xu, Si-Da Han, Can Zhang, et al.
   Journal: Science Advances, October 2020.
   Summary: Identifies FAM171A2 as a regulator of CSF progranulin levels and a genetic modifier of AD, PD, and FTD risk.
2. “Neuronal FAM171A2 mediates α-synuclein fibril uptake and drives Parkinson’s disease.”
   Authors: Jin-Tai Yu, Wei Xu, Si-Da Han, et al.
   Journal: Science, February 2025.
   Summary: Demonstrates FAM171A2’s central role in neuronal uptake of α-synuclein fibrils; inhibition of the protein reduces PD pathology.
3. “The role of FAM171A2-GRN-NF-κB pathway in TBBPA-induced neurotoxicity in HT22 cells.”
   Journal: Chemosphere, January 2025.
   Summary: Explores how environmental toxins affect the FAM171A2-GRN axis, contributing to cellular stress and neurotoxicity.

This review supports the hypothesis that FAM171A2 plays a mechanistic role in PD development and may represent a promising but underexplored therapeutic target.