Neuronal Sigma-1 Receptors: Signaling Functions and Protective Roles in Neurodegenerative Diseases

Sigma-1 receptors (S1R) are ER membrane proteins whose altered function or expression is linked to neurodegenerative disorders including amyotrophic lateral sclerosis/frontotemporal dementia, Alzheimer’s, and Huntington’s disease. S1R agonists are presented as broadly neuroprotective, with protection attributed to multiple signaling roles that are generally pro-survival and anti-apoptotic. The review emphasizes that S1R acts by binding and modulating many client proteins, including ion channels in both ER and plasma membranes, which can influence excitotoxicity and neuronal homeostasis. Mechanistically, the review highlights additional layers of control: effects on trafficking of ion channels at the cell surface, regulation of lipid and protein trafficking, cholesterol binding in lipid rafts, and modulation of calcium flux at the mitochondrial-associated membrane (MAM) to affect mitochondrial stability and cellular bioenergetics. The article also covers therapeutic and disease-specific implications, including discussion of pridopidine’s mechanism in HD.