For the past several years, fundamental research on Sigma-1R (S1R) protein has unveiled its necessity for maintaining proper cellular homeostasis through modulation of calcium and lipid exchange between the endoplasmic reticulum (ER) and mitochondria, ER-stress response, and many other mechanisms. Most of these processes, such as ER-stress response and autophagy, have been associated with neuroprotective roles. In fact, improving these mechanisms using S1R agonists was beneficial in several brain disorders including neurodegenerative diseases. In this review, we will examine S1R subcellular localization and describe S1R-associated biological activity within these specific compartments, i.e., the Mitochondrion-Associated ER Membrane (MAM), ER–Lipid Droplet (ER–LD) interface, ER–Plasma Membreane (ER–PM) interface, and the Nuclear Envelope (NE). We also discussed how the dysregulation of these pathways contributes to neurodegenerative diseases, while highlighting the cellular mechanisms and key binding partners engaged in these processes.

Neurodegenerative disorders, such as Alzheimer’s, Parkinson’s, and Huntington’s disease, due to their multifaced and complicated nature, remain uncurable and impose substantial financial and human burdens on society. Therefore, developing new innovative therapeutic strategies is vital. In this context, drug repurposing has emerged as a promising avenue to expedite the development of treatments for these challenging conditions. One particularly compelling target in this regard is the chaperone protein sigma-1 receptor (S1R), which has garnered significant attention for its neuroprotective properties. Interestingly, several medications, including fluvoxamine (an antidepressant), dextromethorphan (a cough suppressant), and amantadine (an antiviral), which were initially developed for unrelated indications, have shown encouraging results in neurodegenerative therapy through S1R activation. These findings suggest that existing drugs in pharmacopeias can play an essential role in alleviating neurodegenerative symptoms by modulating S1R, thereby offering a faster route and cost-effective path to clinical applications compared to the de novo development of entirely new compounds. Furthermore, as a synergistic benefit, combining S1R-targeting drugs with other therapeutic agents may also improve treatment efficacy. In this review, we highlight key repurposed drugs targeting S1R and explore their mechanisms of action, shedding light on their emerging therapeutic potential in the fight against neurodegeneration.

Sigma-1R (S1R) is a ubiquitously distributed protein highly expressed in the brain and liver. It acts as a ligand-inducible chaperone protein localized at the endoplasmic reticulum. S1R participates in several signaling pathways that oversee diverse cellular and neurological functions, such as calcium and proteome homeostasis, neuronal activity, memory, and emotional regulation. Despite its crucial functions, S1R expression profile in the brain with respect to age and sex remains elusive. To shed light on this matter, we assessed S1R distribution in the mouse brain across different developmental stages, including juvenile, early adult, and middle-aged mice. Using immunohistochemistry, we found that S1R is predominantly expressed in the hippocampus in juvenile mice, particularly in CA1 and CA3 regions. Notably, S1R is not expressed in the subgranular layer of the dentate gyrus of juvenile mice. We observed dynamic changes in S1R levels during development, with most brain regions showing either an abrupt or gradual decline as mice transition from juveniles to adults. Sexual dimorphism is observed before puberty in the hippocampus and hypothalamus and during adulthood in the hippocampus and cortex.