Comparative Analysis of Competing Hypotheses Regarding the Molecular Pathogenesis of Huntington’s Disease
DOI:
https://doi.org/10.58445/rars.1908Keywords:
Huntington's disease, excitotoxicity, NMDA receptor, mutant huntingtin, aggregate, ubiquitin-proteasome system, inclusion body, cellular neuroscience, biochemistryAbstract
The hallmark molecular mechanism of Huntington’s Disease is neuronal intranuclear inclusion bodies consisting of polyubiquitinated mutant huntingtin (mhtt) aggregates expressing an expanded polyglutamine tract. Aggregate-prone fragments of mhtt bind to several intracellular proteins in addition to the glutamate neurotransmitter receptor N-methyl-D-aspartate (NMDA). This review will detail the molecular and cellular pathways by which mhtt aggregates form clumps in inclusion bodies (IBs) by the impairment of the ubiquitin-proteasome system and the autophagy-lysosome system. It will also review the manner by which intracellular mhtt causes neuronal excitotoxicity via NMDA-receptor mediated excitotoxicity. Numerous studies on models of HD have presented various hypotheses on the pathogenesis of neurodegeneration, such as the debate on whether IB formation is a response mechanism of HD or its cause. This paper will discuss the ongoing debate and suggest future research that may reconcile the competing theories. Finally, this article will highlight current and future therapeutic targets for HD in the context of these pathogenesis theories.
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