Roles of sigma-1 receptors on mitochondrial functions relevant to neurodegenerative diseases

Abstract

The sigma-1 receptor (Sig-1R) is a chaperone that resides mainly at the mitochondrion-associated endoplasmic reticulum (ER) membrane (called the MAMs) and acts as a dynamic pluripotent modulator in living systems. At the MAM, the Sig-1R is known to play a role in regulating the Ca2+ signaling between ER and mitochondria and in maintaining the structural integrity of the MAM. The MAM serves as bridges between ER and mitochondria regulating multiple functions such as Ca2+ transfer, energy exchange, lipid synthesis and transports, and protein folding that are pivotal to cell survival and defense. Recently, emerging evidences indicate that the MAM is critical in maintaining neuronal homeostasis. Thus, given the specific localization of the Sig-1R at the MAM, we highlight and propose that the direct or indirect regulations of the Sig-1R on mitochondrial functions may relate to neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD) and amyotrophic lateral sclerosis (ALS). In addition, the promising use of Sig-1R ligands to rescue mitochondrial dysfunction-induced neurodegeneration is addressed.

Systematic In‐Depth Proteomic Analysis of Mitochondria‐Associated Endoplasmic Reticulum Membranes in Mouse and Human Testes

“…In recent years, MAM has aroused tremendous interest in science, especially in the field of neuron and cancer. Several studies have linked defective MAM to some major neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD), and Huntington's disease (HD) . In this regard, MAM alteration is associated with many neurodegenerative diseases.…”

“…Some MAM localized proteins take essential roles in the UPR, such as vesicle‐associated membrane protein‐associated protein B (VAPB), whose mutations cause the devastating disease ALS . Additionally, a variety of ER chaperones involved in protein folding are present in MAM, including Calnexin, Calreticulin, BiP, ERp44, ERp57, and the Sigma 1 receptor (SIGMA1R), among which mutations in SIGMA1R have been identified in frontotemporal lobar degeneration co‐occurring with ALS (FTLD‐ALS) . The Sigma1r knockout mice displayed locomotor deficits associated with muscle weakness, axonal degeneration, and motor neuron loss .…”

Identification of Repurposable Cytoprotective Drugs in Vanishing White Matter Disease Patient-Derived cells

“…The recent demonstration of mitochondrial dysfunction and ine cient respiration in murine models of VWMD (11) has expanded the search for possible therapeutics to include mitochondrial protective compounds and antioxidants. The sigma-1 receptor is a chaperone protein in ER membranes that governs a range of cellular processes, including calcium homeostasis and reactive oxygen species accumulation (26). However, in our study, the cytoprotective effect of the sigma-1 receptor agonists, AVex-73 and amitriptyline, was limited at higher concentrations (≥5 µM; Figures 2, S5).…”

Development of Diagnostic and Therapeutic Probes with Controlled Pharmacokinetics for Use in Radiotheranostics

“…42,43) Since the sigma-1 receptor is related to functions of the central nervous system, such as signal transduction, memory, recognition, and emotion, determining the expression level of the sigma-1 receptor should be useful for diagnosis of neurodegenerative diseases, such as Alzhei mer's, Parkinson's diseases, and amyotrophic lateral sclerosis. [44][45][46] The sigma-1 receptor is also highly expressed in various cancer cells. 47) Sigma-1 receptor agonists and antagonists have been candidates as drugs for the sigma-1 related diseases mentioned above.…”