Biological And Biochemical Characterization Of Sigma Receptors

National Institute On Drug Abuse

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Abstract

Since my laboratory at the NIDA IRP identified the sigma-1 receptor in 1982, many preclinical studies have shown that sigma-1 receptors and associated ligands are involved in stroke, amnesia, depression, cancer, Alzheimer disease, pain, and cocaine addiction. In this fiscal year from Oct 1/2021-Sept 30/2022, we discovered two mechanisms of action of the sigma-1 receptor: (A) The sigma-1 receptor plays a critical role in a survival mechanism called autophagy; and (B) The sigma-1 receptor is pivotal in a clinically unmet disease called the Wolfram's Syndrome. Findings are explained as follows. (A) Macroautophagy/autophagy is an essential process for cellular survival and is implicated in many diseases. A critical step in autophagy is the transport of the transcription factor TFEB from the cytosol into the nucleus, through the nuclear pore (NP) by KPNB1/importin1. In the C9orf72 subtype of amyotrophic lateral sclerosis-frontotemporal lobar degeneration (ALS-FTD), the hexanucleotide (G4C2)RNA expansion (HRE) disrupts the nucleocytoplasmic transport of TFEB, compromising autophagy. Here we show that a molecular chaperone, the SIGMAR1/Sigma-1 receptor (sigma non-opioid intracellular receptor 1), facilitates TFEB transport into the nucleus by chaperoning the NP protein (i.e., nucleoporin) POM121 which recruits KPNB1. In NSC34 cells, HRE reduces TFEB transport by interfering with the association between SIGMAR1 and POM121, resulting in reduced nuclear levels of TFEB, KPNB1, and the autophagy marker LC3-II. Overexpression of SIGMAR1 or POM121, or treatment with the highly selective and potent SIGMAR1 agonist pridopidine, currently in phase 2/3 clinical trials for ALS and Huntington disease, rescues all of these deficits. Our results implicate nucleoporin POM121 not merely as a structural nucleoporin, but also suggest the use of SIGMAR1 agonists, such as pridopidine, for therapeutic development of diseases in which autophagy is impaired. (B) The Wolfram syndrome is a rare autosomal recessive disease affecting many organs with life-threatening consequences and currently no treatment is available. Therefore, the aim of this study was to identify and propose a novel relevant therapy. The pathology is related to the deficient activity of wolframin, an endoplasmic reticulum (ER) transmembrane protein involved in contacts between ER and mitochondria termed mitochondria associated-ER membranes (MAMs). Inherited mutations usually reduce the proteins stability, altering its homeostasis and ultimately reducing ER to mitochondria Ca2+ transfer resulting in mitochondrial dysfunction and cell death. We here demonstrate that activation of the sigma-1 receptor (S1R), an endoplasmic reticulum resident protein involved in Ca2+ transfer, could counteract the functional alterations of MAMs due to wolframin deficiency. The S1R agonist PRE-084 restored Ca2+ transfer and mitochondrial respiration in vitro and was able to alleviate the behavioral symptoms observed in the genetic animal models of the disease, i.e. hyperlocomotion in Wfs1abKO zebrafish and memory deficits and anxiety in Wfs1Exon8 mice. Our findings provide a new therapeutic strategy for Wolfram syndrome patients, by efficiently boosting MAM function using the ligand operated S1R chaperone. Moreover, such strategy could be expanded to other degenerative and mitochondrial diseases involving MAMs dysfunction.