Pharmacological and Pathological Implications of Sigma-1 Receptor in Neurodegenerative Diseases

Abstract

Originally identified as a potential receptor for opioids, the sigma-1 receptor is now recognized as an intracellular chaperone protein associated with mitochondria-associated membranes at the endoplasmic reticulum (ER). Over the past two decades, extensive research has revealed that the sigma-1 receptor regulates many cellular processes, such as calcium homeostasis, oxidative stress responses, protein folding, and mitochondrial function. The various functions of the sigma-1 receptor highlight its role as a central modulator of neuronal health and may be a promising pharmacological target across multiple neurodegenerative conditions. Herein, we provide an overview of the current pharmacological understanding of the sigma-1 receptor with an emphasis on the signaling mechanisms involved. We examine its pathological implications in common neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis. We then highlight how sigma-1 receptor modulation may influence disease progression as well as potential pharmacological mechanisms to alter disease outcomes. The translational potential of sigma-1 receptor therapies is discussed, as well as the most up-to-date results of ongoing clinical trials. This review aims to clarify the therapeutic potential of the sigma-1 receptor in neurodegeneration and guide future research in these diseases.

Keywords: Alzheimer’s disease; ER stress; TMEM97; amyotrophic lateral sclerosis; neurodegenerative disorders; sigma receptor; sigma-1 receptor.

Figure 1

Structural framework of the review: from S1R biology to therapeutic application in neurological disease. Abbreviations: S1R, Sigma-1 receptor; TBI, traumatic brain injury; ALS, amyotrophic lateral sclerosis.

Figure 2

S1R localization, activation, and downstream interactions. Under basal conditions, S1R resides at the mitochondria-associated endoplasmic reticulum membrane (MAM), tethered to BiP. Upon ER stress, S1R dissociates from BiP and binds to inositol 1,4,5-triphosphate receptors, facilitating calcium signaling between the ER and mitochondria. Activated S1R translocates to other compartments, such as the plasma membrane. S1R can modulate ion channels, NMDA receptors, and G-protein coupled receptors. These downstream interactions mediate calcium homeostasis as well as reductions in ER dysfunction and oxidative stress. S1R is implicated in therapeutic benefits for the brain, heart, liver, and kidney. Abbreviations: S1R, Sigma-1 receptor; MAM, mitochondria-associated membrane; BiP, binding immunoglobulin protein; ER, endoplasmic reticulum; IP3, inositol 1,4,5-triphosphate; NMDA, N-methyl-D-aspartate. Figure created using Servier Medical Art (CC BY 3.0 license).

Figure 3

Role of S1R in nervous system injury. Events such as ischemic stroke and TBI trigger a cascade of processes such as BBB breakdown, microglial activation, and neuronal apoptosis. These are mediated through ER stress, spreading depolarizations, and neuroinflammation. Activation of S1R reduces these mechanisms and promotes neuroprotection. Several S1R modulators have been studied in preclinical models and demonstrate beneficial effects. Abbreviations: S1R, Sigma-1 receptor; TBI, traumatic brain injury; BBB, blood–brain barrier; ER, endoplasmic reticulum; IL1-β, interleukin-1 beta; IL-6, interleukin-6; TNF-α, tumor necrosis factor alpha; p-PERK, phosphorylated protein kinase RNA-like ER kinase; p-IRE1α, phosphorylated inositol-requiring enzyme 1 alpha; JNK, c-Jun N-terminal kinase; BDNF, brain-derived neurotrophic factor; CNPase, 2′,3′-cyclic-nucleotide 3′-phosphodiesterase; MOG, myelin oligodendrocyte glycoprotein; PDGFRα, platelet-derived growth factor receptor alpha. Figure created using Servier Medical Art (CC BY 3.0 license).

Figure 4

Proposed protective mechanisms and pharmaceutical implications of sigma-1 receptor in Alzheimer’s disease. This schematic illustrates the progression of AD driven by the deposition of amyloid plaques in the nervous system. S1R activation modulates several key processes in AD pathogenesis to slow cognitive decline and disease progression. Abbreviations: S1R, Sigma-1 receptor; AD, Alzheimer’s disease; NFkB, nuclear factor kappa B; TNFα, tumor necrosis factor alpha; IL-6, interleukin-6; Bax, Bcl-2-associated X protein; MAM, mitochondria-associated membrane; ERK, extracellular signal-regulated kinase; Akt, protein kinase B. Figure created using Servier Medical Art (CC BY 3.0 license).

Figure 5

Disease-specific pathways of Sigma-1 receptor activation in various neurodegenerative diseases. In PD, S1R activation protects dopaminergic neurons and counteracts alpha-synuclein accumulation. In ALS, S1R reduces SOD1 and RAN accumulation, preventing the loss of motor neurons. In HD, S1R helps prevent degeneration of the striatum by relieving ER stress and stimulating neurotrophic proteins. Abbreviations: S1R, Sigma-1 receptor; GDNF, glial cell-derived neurotrophic factor; BDNF, brain-derived neurotrophic factor; ERK, extracellular signal-regulated kinase; GR, glucocorticoid receptor; D1R, dopamine D1 receptor; cAMP, cyclic adenosine monophosphate; TFEB, transcription factor EB; RAN, repeat-associated non-AUG. Figure created using Servier Medical Art (CC BY 3.0 license).