Post-Translational Variants of Major Proteins in Amyotrophic Lateral Sclerosis Provide New Insights into the Pathophysiology of the Disease

Abstract

Post-translational modifications (PTMs) affecting proteins during or after their synthesis play a crucial role in their localization and function. The modification of these PTMs under pathophysiological conditions, i.e., their appearance, disappearance, or variation in quantity caused by a pathological environment or a mutation, corresponds to post-translational variants (PTVs). These PTVs can be directly or indirectly involved in the pathophysiology of diseases. Here, we present the PTMs and PTVs of four major amyotrophic lateral sclerosis (ALS) proteins, SOD1, TDP-43, FUS, and TBK1. These modifications involve acetylation, phosphorylation, methylation, ubiquitination, SUMOylation, and enzymatic cleavage. We list the PTM positions known to be mutated in ALS patients and discuss the roles of PTVs in the pathophysiological processes of ALS. In-depth knowledge of the PTMs and PTVs of ALS proteins is needed to better understand their role in the disease. We believe it is also crucial for developing new therapies that may be more effective in ALS.

Keywords: ALS; FUS; SOD1; TBK1; TDP-43; post-translational modifications.

Figure 1

Functional consequences of PTV (chemical modification or cleavage): WT protein or mutated protein (pathological variant) with a new PTV (black dots) and consequences on protein interaction, function, localization, and half-life.

Figure 2

Schematic representations of SOD1, TDP-43, FUS, and TBK, with their post-translational modification sites.