A New Driver of Parkinson’s Disease: FAM171A2 Facilitates α-Synuclein Uptake and Spread

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder after Alzheimer’s disease (AD), and currently, no disease-modifying therapies are available [1]. A key pathological hallmark of PD is the presence of Lewy bodies, which are primarily composed of aggregated α-synuclein (α-syn) [2]. The misfolding, self-aggregation, and inter-neuronal propagation of pathological α-syn, likely via a prion-like mechanism, are thought to drive the progressive degeneration of dopaminergic neurons and contribute to disease progression [3]. However, the molecular mechanisms governing the neuronal uptake and inter-neuronal transmission of α-syn remain inadequately understood.

A recent study by Yu’s team, published in Science, identified Family with Sequence Similarity 171 Member A2 (FAM171A2) as a PD risk gene and a key mediator of α-syn propagation between neurons. For the first time, they delineated the molecular binding mechanism between FAM171A2 and α-syn and discovered a potential therapeutic candidate capable of disrupting this interaction. These findings provide significant mechanistic insights into the inter-cellular transmission of α-syn in PD and highlight FAM171A2 as a potential therapeutic target for disease intervention (Fig. 1).

Fig. 1.

Schematic representation illustrating FAM171A2 as a novel driver of PD through facilitating α-syn uptake and propagation. A A large-scale meta-GWAS involving over one million individuals identified FAM171A2 as a gene significantly associated with PD susceptibility. This association was further supported by evidence from immunohistochemical analyses of postmortem brain tissue and proteomic data from large CSF cohorts. B In vivo studies revealed that FAM171A2 regulates α-syn pathology and neurotoxicity in mouse models of pathological α-syn propagation. C In vitro assays revealed that FAM171A2 directly binds to α-syn fibrils and mediates their endocytic uptake. Structural analyses identified electrostatic interactions between Domain 1 of FAM171A2 and the C-terminal region of α-syn as the molecular basis for this internalization process. Moreover, Bemcentinib was identified as a potential small-molecule inhibitor that disrupts the FAM171A2–α-syn interaction. The figure was created with BioRender.com.

FAM171A2 is predicted to be an integral membrane protein, whose biological function remained largely uncharacterized until recent studies by Yu’s team revealed its involvement in neurodegenerative processes [4, 5]. The gene displays tissue-enhanced expression in the central nervous system, indicating a potential role in neurological function. In prior work, Yu’s group identified FAM171A2 as a key regulator of progranulin (PGRN), a glycoprotein implicated in the pathogenesis of several neurodegenerative diseases [4]. Notably, the single-nucleotide polymorphism (SNP) rs708384 within FAM171A2 was found to be associated with increased susceptibility to PD [4]. In the present study, the authors expanded their investigation by conducting a large-scale meta–genome-wide association study (GWAS) involving more than one million participants, comprehensively assessing the associations between common variants in FAM171A2 and PD risk [5]. The disease relevance of FAM171A2 was further validated through immunohistochemical analysis of postmortem human brain tissues and correlational studies in cerebrospinal fluid (CSF) samples from PD patients [5]. Elevated FAM171A2 level in CSF was significantly associated with increased pathological α-syn aggregation, reinforcing its potential role in PD pathogenesis (Fig. 1A). Overall, this work exemplifies a robust data-driven approach consisting of an unbiased and large-scale GWAS leading to the identification of FAM171A2, a previously uncharacterized neuronal membrane protein, as a novel factor associated with PD risk. Its relevance was substantiated by consistent findings across postmortem brain tissue and large-scale CSF datasets, highlighting both the reliability of this strategy and its potential for uncovering new pathogenic mechanisms.

Further, their in vivo experiments demonstrated that FAM171A2 modulates α-syn pathology and neurotoxicity in mouse models of α-syn propagation (Fig. 1B) [5]. Overexpression of FAM171A2 exacerbated α-syn preformed-fibril (PFF) induced pathology, leading to greater accumulation of α-syn aggregates, increased loss of tyrosine hydroxylase-positive neurons, and more severe behavioral deficits [5]. In contrast, the knockdown of FAM171A2 reduced α-syn pathology and conferred neuroprotection. Region-specific analysis revealed that FAM171A2 overexpression facilitated the spread of phosphorylated α-syn (p-α-syn) in key regions such as the substantia nigra (SN), striatum, and secondary motor cortex [5]. These findings indicate that neuronal FAM171A2 plays a critical role in mediating the brain-wide spread of α-syn pathology.

To elucidate the mechanism by which FAM171A2 regulates α-syn pathology, Yu’s team conducted a series of in vitro experiments demonstrating that FAM171A2 mediates the endocytosis of α-syn fibrils via direct binding (Fig. 1C) [5]. Immunofluorescence colocalization using total internal reflection fluorescence (TIRF) microscopy indicated that FAM171A2-mediated endocytosis is a principal route for α-syn fibril internalization. Immunoprecipitation confirmed the direct interaction between FAM171A2 and α-syn in cells and PD patients [5]. Domain-mapping analysis further demonstrated that domain 1 (amino acids 30–125) of FAM171A2 is required for α-syn fibril uptake. Nuclear magnetic resonance (NMR) spectroscopy and structural modeling documented electrostatic interactions between FAM171A2 domain 1 and the C-terminal region of α-syn, establishing the structural basis for FAM171A2-mediated α-syn internalization [5]. These mechanistic findings position FAM171A2 as a functionally relevant receptor in α-syn pathology.

Recent studies have increasingly focused on identifying key mediators of α-syn fibril uptake, with particular attention to membrane-associated receptors expressed on neurons or microglia [6–8]. For example, lymphocyte activation gene 3 (LAG3) and amyloid precursor-like protein 1 (APLP1) have been shown to facilitate the endocytosis of α-syn fibrils through binding interactions with their C-terminal region [6]. Additionally, vesicle-associated proteins such as Galectin-3 (GAL3) have been implicated in promoting α-syn aggregation and Lewy body formation within neurons [7]. In addition to neuronal receptors, microglial receptor TREM2 has also been shown to internalize α-syn fibrils. Disruption of TREM2- or lysosomal asparagine endopeptidase-mediated processes reduces α-syn spread, highlighting a microglial mechanism that complements neuronal pathways [8]. However, many previously proposed receptor candidates for α-syn fibril uptake have limited evidence supporting their selective binding to fibrillar α-syn over monomers or lack functional validation in vivo. Yu’s study adds to this area by identifying FAM171A2 as a neuronal membrane receptor that exhibits notable specificity for α-syn fibrils, with structurally complementary binding and functional relevance demonstrated in both cellular and animal models.

In addition to α-syn fibril uptake, some other pathways underlying cell-to-cell transmission of α-syn have been proposed, including exosomal transport and tunneling nanotube-mediated transfer [3]. Multiple membrane proteins, such as low-density lipoprotein receptor-related protein 1 (LRP1) [9] and transmembrane protein 16F (TMEM16F) [10], have been implicated in facilitating the secretion and inter-neuronal spread of pathological α-syn in mouse models of PD. The present study provides important mechanistic insights by identifying a FAM171A2 subdomain that directly binds α-syn fibrils, offering a molecular basis for their intracellular accumulation [5]. While it has been established that FAM171A2 may mediate the propagation of α-syn through receptor-mediated endocytosis, further studies are required to elucidate whether it can also influence α-syn spread through other pathways.

Targeting the interactions between α-syn fibrils and their receptors represents a promising therapeutic strategy for mitigating α-syn-related pathologies. In this study, virtual screening of approved compounds identified bemcentinib—a cancer therapeutic—as a potential inhibitor of the FAM171A2–α-syn interaction （Fig. 1C) [5]. Subsequent ELISA and NMR analyses confirmed that bemcentinib binds to the same C-terminal region of α-syn as FAM171A2, thereby competitively blocking their association [5]. Although bemcentinib does not cross the blood-brain barrier, intracerebroventricular administration in mice effectively reduced α-syn uptake in the SN without inducing neurotoxicity. Extending a similar approach, Liu’s team [11] further identified Givinostat (GS) as another potent inhibitor capable of disrupting the interaction between α-syn fibrils and key receptors such as LAG3 and RAGE [11]. GS was found to bind directly to the intrinsically C-terminal region of both α-syn monomers and fibrils, thereby preventing their engagement with these receptors [11]. Together, these findings highlight the therapeutic potential of targeting receptor-mediated α-syn interactions, particularly FAM171A2, as a viable approach to suppress pathological α-syn propagation in PD.

Despite notable progress in deciphering the pathophysiological mechanisms of PD, several critical questions remain unresolved. A key challenge is the understanding of the molecular basis of the selective vulnerability of dopaminergic neurons to α-syn pathology. One important future direction is to determine whether FAM171A2 exerts a cell-type-specific function in dopaminergic neurons for α-syn propagation. In parallel, it is essential to elucidate whether FAM171A2 is expressed or functional in non-neuronal cell populations, such as microglia and astrocytes, and if so, how it may influence α-syn dynamics in these contexts. These studies would clarify whether FAM171A2 represents a neuron-specific mediator or a broader regulator of α-syn transmission across brain cell types. From a translational perspective, evaluating FAM171A2 expression in individuals at prodromal or early stages of PD could help define its biomarker potential and assist in identifying optimal windows for therapeutic intervention. Ultimately, a deeper mechanistic understanding of FAM171A2 biology could support the development of targeted strategies to block α-syn propagation and modify the disease progression.

In summary, this study uncovers a novel mechanism of α-syn propagation by identifying FAM171A2 as a key mediator in PD [5]. Delineating the molecular interaction between FAM171A2 and α-syn provides important insights into the processes governing neuronal uptake and intracellular accumulation of α-syn. These findings establish a compelling foundation for the development of targeted therapeutic strategies aimed at modifying disease progression in PD.

Conflict of interest

The authors declare no conflict of interest.