Cysteine Modifications in the Pathogenesis of ALS

Abstract

Several proteins are found misfolded and aggregated in sporadic and genetic forms of amyotrophic lateral sclerosis (ALS). These include superoxide dismutase (SOD1), transactive response DNA-binding protein (TDP-43), fused in sarcoma/translocated in liposarcoma protein (FUS/TLS), p62, vasolin-containing protein (VCP), Ubiquilin-2 and dipeptide repeats produced by unconventional RAN-translation of the GGGGCC expansion in C9ORF72. Up to date, functional studies have not yet revealed a common mechanism for the formation of such diverse protein inclusions. Consolidated studies have demonstrated a fundamental role of cysteine residues in the aggregation process of SOD1 and TDP43, but disturbance of protein thiols homeostatic factors such as protein disulfide isomerases (PDI), glutathione, cysteine oxidation or palmitoylation might contribute to a general aberration of cysteine residues proteostasis in ALS. In this article we review the evidence that cysteine modifications may have a central role in many, if not all, forms of this disease.

Structural Insights Into TDP-43 and Effects of Post-translational Modifications

“…Oxidative stress is a hallmark feature of neurodegenerative diseases and ALS was suggested as a cysteninopathia, an aberration of cysteine residues modifications (Valle and Carrì, 2017). It has been hypothesized that the generation of ROS could trigger some TDP-43 pathology (Cohen et al, 2012).…”

Tdp-43 self-interaction is modulated by redox-active compounds auranofin, chelerythrine and riluzole

“…Specifically, it is thought that the C-terminal redox-active Cys-495/ SeCys-496 center of thioredoxin reductase is the target of auranofin 23,27 . Six cysteine residues have been also described in TDP-43 protein, four of which (Cys173, Cys175, Cys198 and Cys244) are located in the two RRM domains, while the other two (Cys39 and Cys50) are in the N-terminal domain 28 . Oxidation of cysteines located in the two RRMs decreases protein solubility, and leads to the formation of intra-and inter-molecular disulfide linkage 29,30 .…”

Antioxidant Alternatives in the Treatment of Amyotrophic Lateral Sclerosis: A Comprehensive Review

“…Several factors have been identified related to the pathogenesis of ALS: OS, mitochondrial dysfunction, neuroinflammation, excitotoxicity due to an increase in the neurotransmitter glutamate, defect in axonal transmission and in the metabolism of RNA, apoptosis, cytoskeletal abnormalities, disruption of membrane trafficking, endoplasmic reticulum stress, protein misfolding and aggregation (Papadimitriou et al, 2010;Blokhuis et al, 2013;Peters et al, 2015;Bond et al, 2018;Yusuf et al, 2018) and cysteine modifications like oxidation or palmitoylation that contribute to a general aberration of cysteine residues proteostasis (Valle and Carrì, 2017). A relationship has been established between environmental conditions and the epidemiology of ALS: alcohol, tobacco, sedentary lifestyle, fungal and viral infections or exposure to electromagnetic radiation (Yu et al, 2014).…”