Abstract
Amyotrophic lateral sclerosis (ALS) is the most common motor neuron degenerative disease in adults and has also been proven to be a type of conformational disease associated with protein misfolding and dysfunction. To date, more than 150 distinct genes have been found to be associated with ALS, among which Superoxide Dismutase 1 (SOD1) is the first and the most extensively studied gene. It has been well-established that SOD1 mutants-mediated toxicity is caused by a gain-of-function rather than the loss of the detoxifying activity of SOD1. Compared with the clear autosomal dominant inheritance of SOD1 mutants in ALS, the potential toxic mechanisms of SOD1 mutants in motor neurons remain incompletely understood. A large body of evidence has shown that SOD1 mutants may adopt a complex profile of conformations and interact with a wide range of client proteins. Here, in this review, we summarize the fundamental conformational properties and the gained interaction partners of the soluble forms of the SOD1 mutants which have been published in the past decades. Our goal is to find clues to the possible internal links between structural and functional anomalies of SOD1 mutants, as well as the relationships between their exposed epitopes and interaction partners, in order to help reveal and determine potential diagnostic and therapeutic targets.
Highlights
Amyotrophic lateral sclerosis (ALS), referred to as Lou Gehrig’s disease, is an adult-onset relentless neurodegenerative disease
Considering the features of NF-L mRNA binding, these results suggest that the binding region where Superoxide Dismutase 1 (SOD1) mutant binds to the NF-L mRNA 3′-untranslated region (UTR) is not the dimer interface since it is occupied by TDP-43
While no decrease in KIF5A-mediated anterograde transport was detected, the anterograde transport of dynein heavy chain as cargo was observed in pre-symptomatic G93A mice, implying that SOD1 mutants might only interact with and interfere with some kinesin members which in turn could result in the impairment of a selective subset of cargos
Summary
Amyotrophic lateral sclerosis (ALS), referred to as Lou Gehrig’s disease, is an adult-onset relentless neurodegenerative disease. The adoption of a dimeric form by these site mutants in a crystal might be explained by the fact that the local changes induced by the site mutations are insufficient to prevent the occurrence of dimerization They may cause a retardation of the dimerization and/or changes in the global structure of the molecule which will lead to a reorientation or shift of the dimer interface [37] and/or ß sheets [30], resulting in an exposure of toxic epitopes such as DBR, etc. These dimeric conformations usually represent rearranged forms occurring due to site mutations and are themselves unstable
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