Sigma 1 receptor as a therapeutic target for amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is an adult disease causing a progressive loss of upper and lower motoneurons, muscle paralysis and early death. ALS has a poor prognosis of 3–5 years after diagnosis with no effective cure. The aetiopathogenic mechanisms involved include glutamate excitotoxicity, oxidative stress, protein misfolding, mitochondrial alterations, disrupted axonal transport and inflammation. Sigma non‐opioid intracellular receptor 1 (sigma 1 receptor) is a protein expressed in motoneurons, mainly found in the endoplasmic reticulum (ER) on the mitochondria‐associated ER membrane (MAM) or in close contact with cholinergic postsynaptic sites. MAMs are sites that allow the assembly of several complexes implicated in essential survival cell functions. The sigma 1 receptor modulates essential mechanisms for motoneuron survival including excitotoxicity, calcium homeostasis, ER stress and mitochondrial dysfunction. This review updates sigma 1 receptor mechanisms and its alterations in ALS, focusing on MAM modulation, which may constitute a novel target for therapeutic strategies. LINKED ARTICLES This article is part of a themed issue on Neurochemistry in Japan. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.6/issuetoc

The role of sigma-1 receptor in organization of endoplasmic reticulum signaling microdomains

“…We demonstrated that ALS-causing E102Q variant acts as a lossof-function mutant that disrupts S1R targeting to MAMs (Fig 1A). S1R is considered to be a potential drug target for treatment of neurodegenerative disorders and cancer (Herrando-Grabulosa et al, 2020;Kim & Maher, 2017;Maurice & Goguadze, 2017;Maurice & Su, 2009;Nguyen et al, 2017;D. A. Ryskamp et al, 2019).…”

“…A. Ryskamp et al, 2019). S1R agonists demonstrated neuroprotective effects in a variety of neurodegenerative disease models and are currently in clinical trials for a variety of neurological disorders including AD, HD, ALS, PD (Brimson, Brimson, Chomchoei, & Tencomnao, 2020;Herrando-Grabulosa et al, 2020;Maurice & Goguadze, 2017;Reilmann et al, 2019;D. A. Ryskamp et al, 2019).…”

“…Hong, Wang, Zhang, Zhang, & Chen, 2017;Mavlyutov et al, 2013;Wang, Saul, Cui, Roon, & Smith, 2017). S1R is considered to be a potential drug target for treatment of neurodegenerative disorders and cancer (Herrando-Grabulosa, Gaja-Capdevila, Vela, & Navarro, 2020;Kim & Maher, 2017;D. A. Ryskamp et al, 2019).…”

Human Paraoxonase-2 (PON2): Protein Functions and Modulation

“…ALS is a multifactorial disease characterized by cerebral cell dysfunction and mitochondrial alteration. It is associated with the progressive increase in neuroinflammation, generalized oxidative stress, and metabolic alterations [186,187]. Saeed et al [188] identified high linkage disequilibrium in PON2 and PON3 genes.…”

Recent advances in the pathogenesis and therapeutics of amyotrophic lateral sclerosis

“…They act as chaperone proteins and modulate essential processes for motor neuron survival, so that targeting these receptors may be a useful way to reduce the death of these neurons. This is extensively addressed in the review by Xavier Navarro and coworkers, which seeks to validate the neuroprotective properties of different ligands for these receptors (Herrando‐Grabulosa, Gaja‐Capdevila, Vela, & Navarro, 2020).…”