Abstract
Huntington’s disease (HD) is a rare neurodegenerative disorder caused by an expansion of CAG trinucleotide repeat located in the exon 1 of Huntingtin (HTT) gene in human chromosome 4. The HTT protein is ubiquitously expressed in the brain. Specifically, mutant HTT (mHTT) protein-mediated toxicity leads to a dramatic degeneration of the striatum among many regions of the brain. HD symptoms exhibit a major involuntary movement followed by cognitive and psychiatric dysfunctions. In this review, we address the conventional role of wild type HTT (wtHTT) and how mHTT protein disrupts the function of medium spiny neurons (MSNs). We also discuss how mHTT modulates epigenetic modifications and transcriptional pathways in MSNs. In addition, we define how non-cell autonomous pathways lead to damage and death of MSNs under HD pathological conditions. Lastly, we overview therapeutic approaches for HD. Together, understanding of precise neuropathological mechanisms of HD may improve therapeutic approaches to treat the onset and progression of HD.
Highlights
Several studies have shown that the biochemical defect and impairment of neuronal energy metabolism in Huntington’s disease (HD) patients are caused by mitochondrial dysfunction, where mitochondria is a major contributor of energy production and a regulator of intracellular signaling and survival [26,27]
N-methyl-D-aspartate receptor (NMDAR) response in the corticostriatal synapse is rescued to normal state by astrocyte-specific reduction of mutant HTT (mHTT) in BACHD mice [67]
In HD, mHTT interferes with promoter binding of cAMP response element binding protein (CREB) and TATA-binding protein-associated factor (TAF), which regulate the expression of proliferator-activated receptor-gamma coactivator (PGC)-1α
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. HD is considered as a multi-systemic neurodegenerative disease due to skeletal muscle and heart function disturbances with energy metabolism and mitochondrial alterations beyond the brain dysfunction [7]. The mHTT is involved in transcriptional alterations, disruption of intracellular transport, excitotoxicity, collapse of protein degradation mechanisms, mitochondrial dysfunction, and disorders of myelin, which make neurons more susceptible to generic stresses, eventually leading to neuronal death [11,12,13,14]. Several studies have shown that the biochemical defect and impairment of neuronal energy metabolism in HD patients are caused by mitochondrial dysfunction, where mitochondria is a major contributor of energy production and a regulator of intracellular signaling and survival [26,27]. We review the different epigenetic modifications which have key roles in neurotoxicity and neurogenesis impairment, and discuss potential therapeutic strategies for HD
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