Abstract
Neurodegeneration has been predominantly recognized as neuronal breakdown induced by the accumulation of aggregated and/or misfolded proteins and remains a preliminary factor in age-dependent disease. Recently, critical regulating molecular mechanisms and cellular pathways have been shown to induce neurodegeneration long before aggregate accumulation could occur. Although this opens the possibility of identifying biomarkers for early onset diagnosis, many of these pathways vary in their modes of dysfunction while presenting similar clinical phenotypes. With selectivity remaining difficult, it is promising that these neuroprotective pathways are regulated through the ubiquitin-proteasome system (UPS). This essential post-translational modification (PTM) involves the specific attachment of ubiquitin onto a substrate, specifically marking the ubiquitin-tagged protein for its intracellular fate based upon the site of attachment, the ubiquitin chain type built, and isopeptide linkages between different ubiquitin moieties. This review highlights both the direct and indirect impact ubiquitylation has in oxidative stress response and neuroprotection, and how irregularities in these intricate processes lead towards the onset of neurodegenerative disease (NDD).
Highlights
Proper central nervous system (CNS) development plays an essential role in neuroprotection, as any malformation during this intricate process allows for an increased susceptibility to neurodegeneration
huntingtin protein (Htt) levels are evenly dispersed throughout progenitor cells that eventually differentiate into striatum-based cortical neurons, whereas in Huntington’s disease (HD) fetuses, the Htt protein congregates in the apical end-feet of progenitor cells [24]
Classified as a basal ganglia disease, HD phenotypes are typically subtle, with a slow progression, until the patient is unable to move and speak [20]. It can be speculated excess CAG tandem repeats inhibit mutant Htt aggregate clearance and impair essential neurodevelopment-based protein-protein interactions (PPIs) due to conformational changes; this is similar to other neurological diseases that lead to aggregate buildup and mitochondrial defects [27]
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Htt levels are evenly dispersed throughout progenitor cells that eventually differentiate into striatum-based cortical neurons, whereas in HD fetuses, the Htt protein congregates in the apical end-feet of progenitor cells [24] This suggests that Htt may play a role in proper CNS development by ensuring proper motor skill development and coordination through the facilitation of progenitor cell polarity and differentiation during neurogenesis. Classified as a basal ganglia disease, HD phenotypes are typically subtle, with a slow progression, until the patient is unable to move and speak [20] It can be speculated excess CAG tandem repeats inhibit mutant Htt (mHtt) aggregate clearance and impair essential neurodevelopment-based PPIs due to conformational changes; this is similar to other neurological diseases that lead to aggregate buildup and mitochondrial defects [27]. A structural analysis of mHtt in any of these essential developmental proteins can determine if the excess CAG repeats truly alter these PPIs, or even whether downstream activation of other pathways is impaired
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