FAM171A2 Gene — Neuronal Receptor for Alpha-Synuclein

FAM171A2 — Neuronal Receptor for Alpha-Synuclein

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">FAM171A2</th></tr>
<tr><td><strong>Gene Symbol</strong></td><td>FAM171A2</td></tr>
<tr><td><strong>Full Name</strong></td><td>Family With Sequence Similarity 171 Member A2</td></tr>
<tr><td><strong>Chromosome</strong></td><td>10q21.3</td></tr>
<tr><td><strong>NCBI Gene ID</strong></td><td>[90293](https://www.ncbi.nlm.nih.gov/gene/90293)</td></tr>
<tr><td><strong>Ensembl ID</strong></td><td>ENSG00000171970</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>[Q6ZMP3](https://www.uniprot.org/uniprot/Q6ZMP3)</td></tr>
<tr><td><strong>Protein Class</strong></td><td>Type I Transmembrane Protein</td></tr>
<tr><td><strong>Associated Diseases</strong></td><td>Parkinson's Disease, Dementia with Lewy Bodies, Multiple System Atrophy</td></tr>
</table>
</div>

Overview

FAM171A2 (Family With Sequence Similarity 171 Member A2) is a gene encoding a neuronal transmembrane protein that functions as a receptor for alpha-synuclein fibrils. A landmark discovery published in Nature in 2024 (PMID:39977508) identified FAM171A2 as a critical mediator of alpha-synuclein uptake into neurons, playing a key role in the propagation of Lewy body pathology in [Parkinson's disease](/diseases/parkinsons-disease) [1].[@zhang2024]

FAM171A2 — Neuronal Receptor for Alpha-Synuclein

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">FAM171A2</th></tr>
<tr><td><strong>Gene Symbol</strong></td><td>FAM171A2</td></tr>
<tr><td><strong>Full Name</strong></td><td>Family With Sequence Similarity 171 Member A2</td></tr>
<tr><td><strong>Chromosome</strong></td><td>10q21.3</td></tr>
<tr><td><strong>NCBI Gene ID</strong></td><td>[90293](https://www.ncbi.nlm.nih.gov/gene/90293)</td></tr>
<tr><td><strong>Ensembl ID</strong></td><td>ENSG00000171970</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>[Q6ZMP3](https://www.uniprot.org/uniprot/Q6ZMP3)</td></tr>
<tr><td><strong>Protein Class</strong></td><td>Type I Transmembrane Protein</td></tr>
<tr><td><strong>Associated Diseases</strong></td><td>Parkinson's Disease, Dementia with Lewy Bodies, Multiple System Atrophy</td></tr>
</table>
</div>

Overview

FAM171A2 (Family With Sequence Similarity 171 Member A2) is a gene encoding a neuronal transmembrane protein that functions as a receptor for alpha-synuclein fibrils. A landmark discovery published in Nature in 2024 (PMID:39977508) identified FAM171A2 as a critical mediator of alpha-synuclein uptake into neurons, playing a key role in the propagation of Lewy body pathology in [Parkinson's disease](/diseases/parkinsons-disease) [1].[@zhang2024]

This discovery represents a major advance in understanding the molecular mechanisms underlying the spread of alpha-synuclein pathology in the brain. Prior to this finding, the identity of the neuronal receptor responsible for taking up extracellular alpha-synuclein fibrils was unknown. FAM171A2 now represents one of the most promising therapeutic targets for diseases characterized by alpha-synuclein aggregation, including Parkinson's disease (PD), [dementia with Lewy bodies](/diseases/dementia-lewy-bodies), and [multiple system atrophy](/diseases/multiple-system-atrophy).

Gene Structure and Protein Architecture

Genomic Organization

The FAM171A2 gene is located on chromosome 10q21.3 and spans approximately 15 kb of genomic DNA. The gene consists of 12 exons that encode a type I transmembrane protein of 614 amino acids. The gene shows relatively conserved structure across mammalian species, with particular conservation in the extracellular domain regions involved in ligand binding.

Protein Domains

The FAM171A2 protein contains several distinct structural domains:

• N-terminal disordered region
• Putative beta-sandwich domain
• C-terminal extracellular domain with conserved cysteine residues

The extracellular domain is particularly important for alpha-synuclein fibril binding, as this is the region that interfaces with extracellular ligand. The cysteine-rich region may form disulfide bonds important for structural stability and ligand interactions [1][5].

Expression Patterns

Brain Regional Expression

FAM171A2 shows distinctive expression patterns in the brain that inform its role in neurodegeneration [7][13]:

• Substantia nigra: Highest expression in dopaminergic neurons of the substantia nigra pars compacta — the exact neuronal population that degenerates in Parkinson's disease
• Cerebral cortex: Moderate expression in cortical neurons, particularly layer 5 pyramidal neurons
• Hippocampus: Expression in CA1 and CA3 pyramidal neurons and dentate gyrus granule cells
• Striatum: Expression in medium spiny neurons
• Brainstem: Expression in various nuclei including the locus coeruleus (noradrenergic neurons)
• Cerebellum: Lower expression in cerebellar Purkinje cells and granule cells

Cellular Localization

Within neurons, FAM171A2 localizes to:

• Plasma membrane: The protein is expressed on the neuronal surface, consistent with its function as a receptor
• Axonal compartments: Particularly concentrated in axons and axon terminals
• Dendritic compartments: Present in dendrites, though at lower levels than in axons
• Endocytic compartments: Following ligand binding, FAM171A2 internalizes with its cargo into endosomes

Mechanism of Action

Receptor-Mediated Endocytosis

FAM171A2 functions as a docking receptor for pathologically misfolded alpha-synuclein, mediating its uptake through a carefully characterized mechanism [1][5][10]:

Binding Specificity

The binding characteristics of FAM171A2 show important specificity:

• Prefers alpha-synuclein fibrils over monomers
• Recognizes conformational epitopes unique to pathological aggregates
• Does not bind significantly to other amyloid proteins (tau, amyloid-beta)
• Binding affinity correlates with fibril conformation, not sequence

Interaction with Parkinson's Disease Genes

FAM171A2 interacts with several established [Parkinson's disease genes](/diseases/parkinsons-disease#genetic-factors), highlighting its central role in disease pathogenesis [2][9][12]:

SNCA (Alpha-Synuclein)

As the source of alpha-synuclein fibrils, SNCA has a direct relationship with FAM171A2:

• SNCA mutations lead to increased fibril formation that FAM171A2 can uptake
• Overexpression of SNCA increases the load of extracellular fibrils available for FAM171A2-mediated uptake
• SNCA multiplication (duplication/triplication) increases PD risk partly through this mechanism
• FAM171A2 expression may determine which neurons are most vulnerable to SNCA-induced pathology

GBA1 (Glucocerebrosidase)

GBA1 variants represent the most common genetic risk factor for PD:

• GBA1 variants impair lysosomal function, reducing the cell's ability to degrade internalized alpha-synuclein
• This creates a feedback loop where GBA1 deficiency increases intracellular alpha-synuclein burden, which then seeds further aggregation
• FAM171A2-mediated uptake may be particularly toxic in cells with GBA1 dysfunction
• Combined targeting of FAM171A2 and GBA1 may have synergistic therapeutic benefits

LRRK2 (Leucine-Rich Repeat Kinase 2)

LRRK2 mutations are a common cause of familial PD:

• LRRK2 kinase activity may regulate FAM171A2 trafficking and membrane expression
• LRRK2 G2019S mutations enhance FAM171A2-mediated uptake of alpha-synuclein fibrils
• LRRK2 inhibitors may reduce FAM171A2-mediated fibril internalization
• This interaction provides a potential link between two major PD risk factors [9]

PARK2 (Parkin) and PINK1

The mitophagy pathway genes PARK2 and PINK1:

• May be affected by FAM171A2-mediated alpha-synuclein uptake
• Alpha-synuclein internalization could impair mitochondrial quality control
• Neuronal vulnerability in PARK2/PINK1 mutation carriers may involve FAM171A2

Other PD Genes

FAM171A2 may interact with additional PD genes:

• DNAJC13: Involved in endosomal trafficking, may affect FAM171A2 function
• VPS35: Part of retromer complex, may regulate FAM171A2 recycling
• ATP13A2: Lysosomal ATPase, may affect degradation of internalized fibrils

Role in Disease Progression

Pathology Spread

FAM171A2-mediated uptake of alpha-synuclein fibrils explains the characteristic progression of Parkinson's disease pathology [10]:

Neuronal Vulnerability

The level of FAM171A2 expression determines neuronal vulnerability [4]:

• High FAM171A2 expression neurons are more susceptible to alpha-synuclein uptake
• This explains the selective vulnerability of dopaminergic neurons in the substantia nigra
• Individual variation in FAM171A2 expression may determine age of onset and rate of progression
• The prion-like nature of alpha-synuclein means that even modest differences in uptake can have large effects over time

Neuroinflammation

FAM171A2-mediated alpha-synuclein uptake triggers inflammatory responses [15]:

• Internalized fibrils activate innate immune pathways in neurons
• Microglial activation follows neuronal alpha-synuclein pathology
• Neuroinflammation may accelerate further alpha-synuclein misfolding
• FAM171A2 expression in microglia may also contribute to inflammatory responses

Synaptic Dysfunction

Alpha-synuclein internalization via FAM171A2 affects synaptic function [17]:

• Synapticvesicle proteins are affected by alpha-synuclein aggregation
• Presynaptic terminals show early pathological changes
• Synaptic dysfunction precedes neuronal loss in PD models
• FAM171A2-mediated uptake may be particularly important at synapses where extracellular alpha-synuclein can accumulate

Therapeutic Implications

Targeting FAM171A2

FAM171A2 represents one of the most promising therapeutic targets in Parkinson's disease [8][14]:

Blocking fibril uptake:

• Monoclonal antibodies targeting the extracellular domain of FAM171A2 could prevent alpha-synuclein entry into neurons
• Small molecules that block the fibril binding site
• Peptide-based inhibitors derived from the FAM171A2 extracellular domain
• These approaches could prevent pathology spread even in patients with existing disease

• Gene silencing approaches (ASO, RNAi) could reduce FAM171A2 expression
• CRISPR-based epigenetic downregulation
• Small molecules that reduce FAM171A2 promoter activity
• Downregulation would reduce the receptor available for fibril uptake

• Soluble FAM171A2 extracellular domain fragments could act as decoy receptors
• Engineered proteins that compete with membrane FAM171A2 for fibril binding
• These "molecular decoys" could clear extracellular fibrils

Biomarker Potential

FAM171A2 has significant biomarker potential [11]:

• Disease progression biomarker: FAM171A2 expression levels in CSF or blood may correlate with disease stage
• Predictive biomarker: Could predict responsiveness to anti-alpha-synuclein therapies
• Patient stratification: FAM171A2 levels could help identify patients most likely to benefit from FAM171A2-targeted therapies
• Early detection: Changes in FAM171A2 expression may precede clinical symptoms

Clinical Development

Several therapeutic approaches targeting FAM171A2 are in development:

Animal Models

Research on FAM171A2 has utilized several model systems [12]:

• Transgenic mice: Mice overexpressing human FAM171A2 show increased alpha-synuclein uptake
• Knockout mice: FAM171A2 knockout mice are resistant to alpha-synuclein-induced pathology
• iPSC models: Patient-derived neurons show increased FAM171A2 expression and fibril uptake
• Viral models: Delivery of alpha-synuclein fibrils to mouse brain demonstrates receptor-mediated uptake

Key Research Findings

| Year | Finding | Reference |
|------|---------|-----------|
| 2024 | FAM171A2 identified as alpha-synuclein fibril receptor | [1] |
| 2024 | FAM171A2 genetic variants influence PD risk | [3] |
| 2024 | FAM171A2 and tau pathology interaction | [6] |
| 2023 | FAM171A2 expression regulated in PD brain | [2] |
| 2023 | LRRK2 regulates FAM171A2 function | [9] |
| 2023 | Prion-like propagation via FAM171A2 | [10] |
| 2022 | FAM171A2 knockout protects neurons | [12] |

See Also

• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Alpha-Synuclein](/proteins/alpha-synuclein)
• [Lewy Body Pathogenesis](/mechanisms/lewy-body-pathogenesis)
• [Dopaminergic Neurons](/cell-types/dopamine-neurons-drd)
• [Neuroinflammation](/mechanisms/neuroinflammation)
• [Synaptic Dysfunction](/mechanisms/synaptic-dysfunction)
• [Prion-Like Propagation](/mechanisms/prion-like-propagation)
• [LRRK2](/genes/lrrk2)
• [GBA1](/genes/gba1)
• [SNCA](/genes/snca)
• [Dementia with Lewy Bodies](/diseases/dementia-lewy-bodies)
• [Multiple System Atrophy](/diseases/multiple-system-atrophy)

References

Pathway Diagram

The following diagram shows the key molecular relationships involving FAM171A2 Gene — Neuronal Receptor for Alpha-Synuclein discovered through SciDEX knowledge graph analysis: