Altered localization, abnormal modification and loss of function of Sigma receptor-1 in amyotrophic lateral sclerosis

Abstract

Intracellular accumulations of mutant, misfolded proteins are major pathological hallmarks of amyotrophic lateral sclerosis (ALS) and related disorders. Recently, mutations in Sigma receptor 1 (SigR1) have been found to cause a form of ALS and frontotemporal lobar degeneration (FTLD). Our goal was to pinpoint alterations and modifications of SigR1 in ALS and to determine how these changes contribute to the pathogenesis of ALS. In the present study, we found that levels of the SigR1 protein were reduced in lumbar ALS patient spinal cord. SigR1 was abnormally accumulated in enlarged C-terminals and endoplasmic reticulum (ER) structures of alpha motor neurons. These accumulations co-localized with the 20s proteasome subunit. SigR1 accumulations were also observed in SOD1 transgenic mice, cultured ALS-8 patient's fibroblasts with the P56S-VAPB mutation and in neuronal cell culture models. Along with the accumulation of SigR1 and several other proteins involved in protein quality control, severe disturbances in the unfolded protein response and impairment of protein degradation pathways were detected in the above-mentioned cell culture systems. Furthermore, shRNA knockdown of SigR1 lead to deranged calcium signaling and caused abnormalities in ER and Golgi structures in cultured NSC-34 cells. Finally, pharmacological activation of SigR1 induced the clearance of mutant protein aggregates in these cells. Our results support the notion that SigR1 is abnormally modified and contributes to the pathogenesis of ALS.

SIGMAR1 Regulates Membrane Electrical Activity in Response to Extracellular Matrix Stimulation to Drive Cancer Cell Invasiveness

“…[13][14][15][16]51). Indeed, the key mechanisms linking Sig1Rs to neuronal survival involve their translocation from the MAM to plasma membrane, where they bind and modulate ion channels and receptors (14).…”

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).…”

Methyl pyruvate rescues mitochondrial damage caused by SIGMAR1 mutation related to amyotrophic lateral sclerosis

“…Al-Saif et al reported that overexpression of σ 1 R E102Q in NSC34 cells, a motor neuron-like cell line, enhanced vulnerability to ER stress and reduced cell viability [13]. Prause et al also reported abnormal distribution of endogenous σ 1 R in fibroblasts of ALS8 patients (OMIM #608627) [14]. Although these observations suggest that mutation or mislocalization of σ 1 R functions in ALS and FTLD pathologies, it is not known whether perturbations of σ 1 R protein compromise motor neuron survival, and if so, what the underlying mechanism is.…”