FAM171A2: Biological Roles and Therapeutics Strategies

• Gene Information: Human FAM171A2, located on chromosome 17, encodes a single-pass type I transmembrane protein. It was identified as a Parkinson’s disease risk gene through genome-wide association studies.
• Protein Expression: FAM171A2 is enriched in the brain, where it localized to neuronal cell membranes and synapses. Its levels were elevated in PD.
• Signaling Pathway: FAM171A2 functions as a neuronal membrane receptor for pathological α-synuclein fibrils. Its extracellular domain 1 binds the α-syn fibrils, triggering endocytosis and promoting the neuron-to-neuron spread and neurotoxicity of α-syn pathology.
• Therapeutic Application: FAM171A2 is a promising disease-modifying target for PD. Blocking the α-syn fibril–FAM171A2 interaction could halt pathological α-syn uptake and spread. Antibody-based receptor blockade, small-molecule inhibitors and small nucleic acid-based drugs are promising therapeutic strategies for PD treatment.

FAM171A2

• The exons 1-8 of mouse Fam171a2 gene that encode the whole molecule (ATG to STOP codon), including 3’UTR were replaced by human counterparts in B-hFAM171A2 mice.
• The promoter and 5’UTR of the mouse gene are also replaced. The human FAM171A2 expression is driven by human FAM171A2 promoter, while mouse Fam171a2 gene transcription and translation will be disrupted.

Strain specific analysis of FAM171A2 mRNA expression in wild-type C57BL/6JNifdc mice and heterozygous B-hFAM171A2 mice by RT-PCR. Cortex RNA were isolated from wild-type C57BL/6JNifdc mice (+/+) and heterozygous B-hFAM171A2 mice (H/+), then cDNA libraries were synthesized by reverse transcription, followed by PCR with mouse or human FAM171A2 primers. Human FAM171A2 mRNA was detectable only in heterozygous B-hFAM171A2 mice but not in wild-type mice, and the sequences were confirmed via Sanger sequencing. Mouse Fam171a2  mRNA was detectable in wild-type mice and heterozygous B-hFAM171A2 mice.