How does mutant huntingtin affect Huntington Disease?

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Impact of Mutant Huntingtin on Huntington's Disease

Introduction to Huntington's Disease and Mutant Huntingtin

Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the HTT gene, leading to the production of a mutant huntingtin protein (mHTT) . This mutation results in a gain-of-function that is toxic to neurons, particularly in the striatum and cortex, leading to the characteristic motor, cognitive, and psychiatric symptoms of HD .

Mechanisms of Mutant Huntingtin Toxicity

Disruption of Cellular Functions

Mutant huntingtin disrupts several cellular processes, including transcription, proteostasis, and mitochondrial function. It interferes with normal gene expression, leading to transcriptional dysregulation observed in both human HD brains and various mouse models. Additionally, mHTT impairs mitochondrial dynamics, causing mitochondrial fragmentation, defective axonal transport, and synaptic degeneration . These disruptions contribute to neuronal dysfunction and death, exacerbating the progression of HD .

Impaired Immune Cell Function

Mutant huntingtin also affects immune cell function. Studies have shown that mHTT impairs the migration of microglia and other immune cells, which may contribute to the neuroinflammatory environment observed in HD. This impaired migration is linked to defective actin remodeling, further highlighting the widespread impact of mHTT on cellular functions.

Therapeutic Strategies Targeting Mutant Huntingtin

Antisense Oligonucleotides (ASOs)

One promising therapeutic approach involves the use of antisense oligonucleotides (ASOs) to reduce the levels of mHTT. Clinical trials have demonstrated that ASOs can effectively lower mHTT concentrations in the cerebrospinal fluid (CSF) of HD patients, leading to a dose-dependent reduction in mHTT levels without serious adverse events . This reduction in mHTT is associated with decreased HD pathology and improved motor, cognitive, and behavioral phenotypes in preclinical models .

Other Huntingtin-Lowering Strategies

Other strategies to lower huntingtin levels include the use of miRNA and autophagy-based approaches. These methods aim to either reduce the production of mHTT or enhance its clearance from cells. While these approaches are still in the experimental stages, they hold promise for future therapeutic development.

Conclusion

Mutant huntingtin plays a central role in the pathogenesis of Huntington's disease by disrupting various cellular processes and impairing immune cell function. Therapeutic strategies that target the reduction of mHTT levels, such as antisense oligonucleotides, show significant potential in mitigating the effects of HD. Continued research into these and other huntingtin-lowering approaches is crucial for developing effective treatments for this devastating condition.