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Abstract
Amyotrophic lateral sclerosis (ALS) is characterized by the selective degeneration of motor neurons (MNs) and their target muscles. Misfolded proteins which often form intracellular aggregates are a pathological hallmark of ALS. Disruption of the functional interplay between protein degradation (ubiquitin proteasome system and autophagy) and RNA-binding protein homeostasis has recently been suggested as an integrated model that merges several ALS-associated proteins into a common pathophysiological pathway. The E102Q mutation in one such candidate gene, the endoplasmic reticulum (ER) chaperone Sigma receptor-1 (SigR1), has been reported to cause juvenile ALS. Although loss of SigR1 protein contributes to neurodegeneration in several ways, the molecular mechanisms underlying E102Q-SigR1-mediated neurodegeneration are still unclear. In the present study, we showed that the E102Q-SigR1 protein rapidly aggregates and accumulates in the ER and associated compartments in transfected cells, leading to structural alterations of the ER, nuclear envelope and mitochondria and to subsequent defects in proteasomal degradation and calcium homeostasis. ER defects and proteotoxic stress generated by E102Q-SigR1 aggregates further induce autophagy impairment, accumulation of stress granules and cytoplasmic aggregation of the ALS-linked RNA-binding proteins (RBPs) matrin-3, FUS, and TDP-43. Similar ultrastructural abnormalities as well as altered protein degradation and misregulated RBP homeostasis were observed in primary lymphoblastoid cells (PLCs) derived from E102Q-SigR1 fALS patients. Consistent with these findings, lumbar α-MNs of both sALS as well as fALS patients showed cytoplasmic matrin-3 aggregates which were not co-localized with pTDP-43 aggregates. Taken together, our results support the notion that E102Q-SigR1-mediated ALS pathogenesis comprises a synergistic mechanism of both toxic gain and loss of function involving a vicious circle of altered ER function, impaired protein homeostasis and defective RBPs.
Highlights
Several familial ALS and frontotemporal dementia (FTD)-linked mutations affect protein homeostasis and autophagy, including ubiquilin-2 (UBQLN2), p62/SQSTM1, optineurin (OPTN), TANK-binding kinase 1 (TBK1), valosin-containing protein (VCP), charged multivesicular body protein 2B (CHMP2B), vesicle-associated membrane protein B (VAPB) and FIG4.1,2 Recent studies emphasized a functional interplay between autophagy and RNA processing, associating several ALS-FTD genes in a converging pathway leading to insufficient degradation and abnormal aggregation of proteins.[2]
Using PLCs obtained from E102Q-Sigma receptor-1 (SigR1) familial ALS (fALS) patients[7] and autopsy specimens from sporadic ALS (sALS) and fALS patients as well as cell culture models, we found that E102Q-SigR1 aggregates induce ER stress with distinct ER and nuclear envelope alterations, impaired Ca2+ homeostasis and autophagy pathways and aberrant extra-nuclear localization of several ALS-associated RBPs
The P56S mutation in the VAPB gene leads to a form of fALS, ALS-8,35,36 characterized by distinct ultrastructural ER alterations and defective protein degradation pathways.[37]
Summary
Several familial ALS (fALS) and frontotemporal dementia (FTD)-linked mutations affect protein homeostasis and autophagy, including ubiquilin-2 (UBQLN2), p62/SQSTM1 (sequestosome1), optineurin (OPTN), TANK-binding kinase 1 (TBK1), valosin-containing protein (VCP), charged multivesicular body protein 2B (CHMP2B), vesicle-associated membrane protein B (VAPB) and FIG4.1,2 Recent studies emphasized a functional interplay between autophagy and RNA processing, associating several ALS-FTD genes in a converging pathway leading to insufficient degradation and abnormal aggregation of proteins.[2]. Even in sporadic ALS (sALS), toxic aggregates of such proteins in MNs are frequent and can be triggered by defective UPS/autophagy.[4] Aggregation of these RBPs together with other proteins is physiological and reversible (unfolded protein response, UPR).[5] RBPs control RNA polymerase elongation, mRNA maturation, transport and degradation, and regulate transcriptional activity and distribution of RNAs by RNA granule formation. We previously described abnormal modification as well as altered localization of SigR1 protein in sALS patient spinal cord.[11] Mavlyutov et al demonstrated that lack of SigR1 exacerbates ALS progression in G93A-SOD1 mice.[12] SigR1−/ − mice showed MND pathology and symptoms.[13] In vitro, SigR1 depletion causes Ca2+ dysregulation, Cell Death and Differentiation autophagy defects and ER stress-mediated neuronal death.[11,14] a SigR1 agonist improved motor function and MN survival in SOD1 mice.[15] These studies suggest a crucial role of SigR1 for neuronal survival. It is still unclear whether E102Q-SigR1 causes ALS due to a gain or loss of functions
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