Abstract
Huntington’s disease (HD) is an autosomal dominant inherited neurodegenerative disorder characterized by the loss of motor control and cognitive ability, which eventually leads to death. The mutant huntingtin protein (HTT) exhibits an expansion of a polyglutamine repeat. The mechanism of pathogenesis is still not fully characterized; however, evidence suggests that post-translational modifications (PTMs) of HTT and upstream and downstream proteins of neuronal signaling pathways are involved. The determination and characterization of PTMs are essential to understand the mechanisms at work in HD, to define possible therapeutic targets better, and to challenge the scientific community to develop new approaches and methods. The discovery and characterization of a panoply of PTMs in HTT aggregation and cellular events in HD will bring us closer to understanding how the expression of mutant polyglutamine-containing HTT affects cellular homeostasis that leads to the perturbation of cell functions, neurotoxicity, and finally, cell death. Hence, here we review the current knowledge on recently identified PTMs of HD-related proteins and their pathophysiological relevance in the formation of abnormal protein aggregates, proteolytic dysfunction, and alterations of mitochondrial and metabolic pathways, neuroinflammatory regulation, excitotoxicity, and abnormal regulation of gene expression.
Highlights
Introduction toHuntington’s DiseaseProtein misfolding diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and other prion diseases are disorders of the central nervous system (CNS) associated with protein aggregation and toxicity
In all of these diseases, acquisition of an abnormal secondary structure by specific proteins accompanies aggregation, and this structure subsequently propagates in the brain in a prion-like manner [1]. These neurodegenerative diseases are associated with the disturbance of normal cellular processes, including protein translation [2,3], post-translational modification (PTM), protein degradation [4], and mitochondria homeostasis [5]
Endless efforts are made to understand the pathological mechanisms of HD better, to develop new, efficient drugs, which prevent the progression of HD, and to assist in early and accurate diagnosis
Summary
Protein misfolding diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and other prion diseases are disorders of the central nervous system (CNS) associated with protein aggregation and toxicity. These neurodegenerative diseases are associated with the disturbance of normal cellular processes, including protein translation [2,3], post-translational modification (PTM), protein degradation [4], and mitochondria homeostasis [5]. These abnormal cellular processes are all hallmarks of misfolded protein stress. HD is mainly characterized by the intranuclear accumulation of HTT-derived aggregates in the brain cortex and striatum of patients [9] and by neuronal dysfunction This eventually results in the loss of spiny neurons in the striatum and subsequent neuronal damage and cell death. Post-Translational Modifications in Selected Cellular Events of the Diverse Pathomechanism of Huntington’s Disease
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
