Plexin-A1

Plexin-A1 (PLXNA1) is a coreceptor for class 3 semaphorins (SEMA3A, SEMA3C, SEMA3F, and SEMA6D) that modulates cytoskeletal remodeling and cell migration. Its cytoplasmic domain is essential for downstream signaling activation. Beyond semaphorin signaling, it also serves as a coreceptor of TREM2 for SEMA6D in dendritic cells, supporting immune responses and skeletal homeostasis (UniProt: Q9UIW2).

Plexin-A1 has established roles in axon guidance and invasive growth, processes central to neuronal development and function. A rare autosomal recessive neurodevelopmental syndrome, Dworschak-Punetha syndrome (DWOPNED, MIM 619955), is caused by PLXNA1 mutations and presents with global developmental delay, intellectual disability, speech delay, autism spectrum features, and variable brain imaging abnormalities (UniProt: Q9UIW2).

In Alzheimer's disease, Plexin-A1 is significantly downregulated in human post-mortem AD brain compared to age-matched controls (mean log2FC: −0.62, Chaparral AD proteomics). This reduction was observed across 2 of 4 tested subcellular fractions in a TMT-labeled quantitative proteomics study, suggesting a consistent decrease in AD pathology that may impair semaphorin-mediated axon guidance and immune-related functions critical to neuronal health.