Sigmar1’s Molecular, Cellular, and Biological Functions in Regulating Cellular Pathophysiology

Abstract

The Sigma 1 receptor (Sigmar1) is a ubiquitously expressed multifunctional inter-organelle signaling chaperone protein playing a diverse role in cellular survival. Recessive mutation in Sigmar1 have been identified as a causative gene for neuronal and neuromuscular disorder. Since the discovery over 40 years ago, Sigmar1 has been shown to contribute to numerous cellular functions, including ion channel regulation, protein quality control, endoplasmic reticulum-mitochondrial communication, lipid metabolism, mitochondrial function, autophagy activation, and involved in cellular survival. Alterations in Sigmar1’s subcellular localization, expression, and signaling has been implicated in the progression of a wide range of diseases, such as neurodegenerative diseases, ischemic brain injury, cardiovascular diseases, diabetic retinopathy, cancer, and drug addiction. The goal of this review is to summarize the current knowledge of Sigmar1 biology focusing the recent discoveries on Sigmar1’s molecular, cellular, pathophysiological, and biological functions.

Novel Therapeutic Target for Prevention of Neurodegenerative Diseases: Modulation of Neuroinflammation with Sig-1R Ligands

“…The physiological role and the molecular functions of Sig-1R have been recently reviewed [85][86][87]. Sig-1R is a non-opioid, non-G-protein coupled, non-ionotropic, ligandoperated intracellular chaperone that is located in the mitochondrial-associated membrane part (MAM) of the ER membrane.…”

Rapid Molecular Diagnosis of Genetically Inherited Neuromuscular Disorders Using Next-Generation Sequencing Technologies

“…In 2 other patients, we identified a homozygous (P87) and compound heterozygous (P88) deletion in exon 4 of SIGMAR1 . Several publications have associated truncations/deletions in Sigmar1 with the development of distal hereditary motor neuropathies (MIM #605726) [ 46 , 47 ]. Unequal crossover due to misalignment during meiosis in the ch17p11.2 region leads to CNVs comprising the PMP22 gene that are associated with either Charcot–Marie–Tooth (CMT1A) disease ( PMP22 duplication) or hereditary neuropathy with liability to pressure palsy (HNLP) diseases ( PMP22 deletion) [ 48 ].…”

The Interplay Between Autophagy and RNA Homeostasis: Implications for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

“…ALS/FTD can be caused by recessive mutations in the SIGMAR1 gene, which encodes the sigma-1 receptor (sig-1R) ( Luty et al, 2010 ). Although sig-1R participates in a broad array of biological functions ( Aishwarya et al, 2021 ), reduced autophagy flux and accumulation of autophagic structures are characteristics of several cell and mouse models of SIGMAR1 -ALS/FTD ( Christ et al, 2020 ). Likewise, pharmacological activation or overexpression of sig-1R can increase autophagy flux in vitro and in vivo ( Gregianin et al, 2016 ; Christ et al, 2019 ).…”