Deciphering the Role of Aberrant Protein Post-Translational Modification in the Pathology of Neurodegeneration

Abstract

: Neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD), are characterized by progressive neuronal dysfunction and death. Current studies have established detrimental modifications in brain protein function as well as structure which stimulate their aggregation, misfolding and deposition in and around the neurons, as an important hallmark of neurodegenerative disorders. Posttranslational modification (PTM) of proteins including phosphorylation, acetylation, glycosylation, palmitoylation, SUMOylation, and ubiquitination are important regulators of protein characteristics including stability, intracellular distribution, activity, interactions, aggregation and clearance. Despite clear evidence that altered protein modifications emerging from impromptu chemical modifications to side chains of amino acid is associated with neurodegeneration, the underlying mechanisms that promote aberrant PTM remain poorly understood. Therefore, elucidating PTM of specific disease associated proteins can prove to be a significant step in evaluating functional alteration of proteins and their association with neurodegeneration. This review describes how aberrant PTM of various proteins are linked with the neurodegenerative disease pathogenesis, as well as molecular strategies targeting these modifications for treating such diseases, which are yet incurable.

Genetic regulation of post-translational modification of two distinct proteins

“…3). The structure of TfGP32 is currently not known, but its genetic association signal colocalises with two plasma glycan traits containing antennary fucose (A4F1G3S[3,3 + 6,3 + 6]3, A4F1G4S [3,3,3,6]4) and overall plasma antennary fucosylation (Supplementary Fig. 4 and Supplementary Results).…”

“…For example, only 18 histone deacetylases target more than 3600 acetylation sites on 1750 proteins 2 . Environmental or pathological conditions can lead to dysregulation of PTM activities, which has been related to aging 3 and several diseases, including cancer, diabetes, and neurodegeneration [4][5][6] . Despite their importance, little is known about the genetic regulation of posttranslational modifications.…”

PSSNet—An Accurate Super-Secondary Structure for Protein Segmentation

“…Medical proteomic research is mainly focused on the extensive study of the molecular basis of a disease associated with the arrival of aberrant forms of proteins that are regularly not found under normal (healthy) conditions. Aberrant proteins are frequently caused by genetic polymorphisms, alternative splicing, and PTMs [ 33 , 34 ]. Such structural changes associated with the disease can be localized in different types of SSSs.…”

The role of s-palmitoylation in neurological diseases: implication for zDHHC family

“…APP, BACE1, and γ-secretase can all be palmitoylated and modified or regulated by palmitoylated proteins. Among them, Cys 186 and Cys 187 of APP can increase the interaction of APP with lipid rafts through palmitoylation, which enhances the gene processing of amyloid proteins and leads to increased γ-secretase-mediated cleavage ( Shafi et al, 2021 ). Palmitoylation of BACE1 occurs at the transmembrane and C-terminal cytoplasmic structural domains of four cysteine residues (Cys474, Cys478, Cys482 and Cys485) ( Shah, 2020 ).…”