Role of sigma-1 receptors in neurodegenerative diseases

Abstract

Neurodegenerative diseases with distinct genetic etiologies and pathological phenotypes appear to share common mechanisms of neuronal cellular dysfunction, including excitotoxicity, calcium dysregulation, oxidative damage, ER stress and mitochondrial dysfunction. Glial cells, including microglia and astrocytes, play an increasingly recognized role in both the promotion and prevention of neurodegeneration. Sigma receptors, particularly the sigma-1 receptor subtype, which are expressed in both neurons and glia of multiple regions within the central nervous system, are a unique class of intracellular proteins that can modulate many biological mechanisms associated with neurodegeneration. These receptors therefore represent compelling putative targets for pharmacologically treating neurodegenerative disorders. In this review, we provide an overview of the biological mechanisms frequently associated with neurodegeneration, and discuss how sigma-1 receptors may alter these mechanisms to preserve or restore neuronal function. In addition, we speculate on their therapeutic potential in the treatment of various neurodegenerative disorders.

Biochemical Pharmacology of the Sigma-1 Receptor

“…The S1R has been established as a therapeutic target for many neurodegenerative conditions in humans that involve various forms of cellular metabolic stress, including amyotrophic lateral sclerosis (Al-Saif et al, 2011;Mancuso et al, 2012;Mavlyutov et al, 2013Mavlyutov et al, , 2015Prause et al, 2013;Gromek et al, 2014;Fukunaga et al, 2015;Mishra et al, 2015), frontotemporal lobar dementia (Luty et al, 2010), Alzheimer disease (Feher et al, 2012;Yin et al, 2015), Parkinson disease (Mishina et al, 2005;Mori et al, 2012), retinal neurodegeneration (Smith et al, 2008;Mavlyutov et al, 2011;Shimazawa et al, 2015), addiction to drugs of abuse (Navarro et al, 2010;Nguyen et al, 2015), and psychiatric disorders (Tsai et al, 2014) (Fig. 1).…”

Aberrant Subcellular Dynamics of Sigma-1 Receptor Mutants Underlying Neuromuscular Diseases

“…In addition, the s-1R is present on nuclear envelopes and enriched at lipid rafts (Hayashi and Su, 2003a,b) where it regulates many cellular functions (Su et al, 2010;Kourrich et al, 2012;Nguyen et al, 2015;Su, 2015). In the absence of agonist, the s-1R is bound to binding immunoglobulin protein (BiP) Hayashi and Fujimoto, 2010), a major ER chaperone protein (Rao and Bredesen, 2004).…”

Activation of Sigma-1 receptor ameliorates anxiety-like behavior and cognitive impairments in a rat model of post-traumatic stress disorder

“…Hypofunction of the Sigma-1 receptor has been indicated to be involved in the pathophysiology of a variety of diseases [7][8][9].…”