Post-Translational Modifications Modulate Proteinopathies of TDP-43, FUS and hnRNP-A/B in Amyotrophic Lateral Sclerosis

Abstract

It has been shown that protein low-sequence complexity domains (LCDs) induce liquid-liquid phase separation (LLPS), which is responsible for the formation of membrane-less organelles including P-granules, stress granules and Cajal bodies. Proteins harbouring LCDs are widely represented among RNA binding proteins often mutated in ALS. Indeed, LCDs predispose proteins to a prion-like behaviour due to their tendency to form amyloid-like structures typical of proteinopathies. Protein post-translational modifications (PTMs) can influence phase transition through two main events: i) destabilizing or augmenting multivalent interactions between phase-separating macromolecules; ii) recruiting or excluding other proteins and/or nucleic acids into/from the condensate. In this manuscript we summarize the existing evidence describing how PTM can modulate LLPS thus favouring or counteracting proteinopathies at the base of neurodegeneration in ALS.

Unraveling the toxic effects mediated by the neurodegenerative disease–associated S375G mutation of TDP-43 and its S375E phosphomimetic variant

“…Nonetheless, the observation that a single phosphorylation event can induce such prominent changes in genes controlled by TDP-43 is an important observation also with regard to the normal function of this protein and supports the notion that even relatively small changes in the post-translational status of TDP-43 can have profound influences on cellular metabolism. Therefore, our data from these variants further support the view that PTMs of TDP-43 might act as powerful modulators in TDP-43 normal functioning and neurodegenerative processes ( 14 , 98 ).…”

Identification ofRNF13as cause of recessively inherited ALS in a multi-case pedigree

“…29 30 33 Various bioinformatics tools predict that the protein also contains a signal peptide, a nuclear localisation signal (NLS), a PEST domain (region with high concentration of proline, glutamic acid, serine and threonine) and low complexity (LC) regions that are regions enriched in charged amino acids that predispose proteins to form amyloid-like structures typical of proteinopathies 29 30 33 42. Genes that encode proteins with LC domains are well represented among ALS-causative genes 43. Presence of RNF13 in the nucleoplasm and various cellular membranes and organelles has been reported 29 31 33 44.…”

The Role of Ubiquitin in Regulating Stress Granule Dynamics

“…In particular, phosphorylation, acetylation, methylation, poly-ADP-ribosylation, ubiquitination and modification by the ubiquitin-like proteins small ubiquitin-related modifier (SUMO) and neural precursor cell expressed developmentally downregulated protein (NEDD) have been implicated in the assembly and disassembly of SGs ( Tourrière et al, 2003 ; Jayabalan et al, 2016 ; Jongjitwimol et al, 2016 ; Tsai et al, 2016 ; Reineke et al, 2017 ; Duan et al, 2019 ; Gal et al, 2019 ; Saito et al, 2019 ; Huang et al, 2020 ; Keiten-Schmitz et al, 2020 ). PTMs affect the physicochemical characteristics of the modified proteins, for example their charge, hydrophobicity, and conformation, which can influence their LLPS behavior by affecting their valency and thus their interaction properties ( Farina et al, 2021 ; Sternburg et al, 2022 ).…”