SIGMAR1 encodes sigma-1 receptor (Sig-1R), a chaperone protein localized to mitochondria-associated endoplasmic reticulum membranes (MAM) with multifaceted cellular functions. Structurally, SigmaR1 oligomers stabilize rough endoplasmic reticulum sheets through amphipathic helix arrays that flatten membrane leaflets and oppose curvature 1. Functionally, SIGMAR1 regulates lipid transport and microdomains while modulating calcium signaling, ion channels, and neurotransmitter release. It facilitates mitochondrial axonal transport in motor neurons and protects against oxidative stress-induced cell death. SIGMAR1 also regulates osteoclastogenesis by promoting ER-associated degradation of SERCA2 2. Pathologically, SIGMAR1 mutations cause distal hereditary motor neuropathy (dHMN) type 2 and juvenile amyotrophic lateral sclerosis type 16, characterized by slowly progressive distal motor weakness 3. The pathogenic E102Q mutation impairs mitochondrial ATP production, inhibits proteasome activity, and exacerbates ER stress-induced neuronal death 4. Clinically, blarcamesine, a SIGMAR1 agonist, significantly slowed cognitive decline in early Alzheimer's disease (36.3% progression reduction at 48 weeks), with greater benefit in wild-type SIGMAR1 carriers (49.8% reduction), supporting SIGMAR1 activation as a therapeutic strategy 5. These findings establish SIGMAR1 as a critical neuroprotective protein with therapeutic potential in neurodegenerative diseases.