Molecular Pathophysiological Mechanisms in Huntington's Disease

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Huntington's disease (HD) is a hereditary neurodegenerative disorder.
• The genetic cause is a CAG repeat expansion in the huntingtin gene (HTT) on chromosome 4.
• Pathogenic mechanisms involve complex molecular cascades leading to neuronal death.

Purpose of the Study:

• To review the pathogenic cascades contributing to neuronal demise in Huntington's disease.
• To highlight the molecular pathways implicated in Huntington's disease pathology.
• To discuss the ongoing search for therapies based on basic research findings.

Main Methods:

• Literature review of research on Huntington's disease.
• Analysis of findings from animal models and in vitro experiments.
• Discussion of molecular mechanisms underlying neuronal loss.

Main Results:

• Mutant huntingtin protein triggers neuronal loss, particularly in striatal medium spiny neurons.
• Key contributors include excitotoxicity, transcriptional dysregulation, mitochondrial dysfunction, oxidative stress, impaired proteostasis, altered axonal transport, and reduced trophic factors.
• Astrocytic dysfunction and neuroinflammation also play roles in HD pathology.

Conclusions:

• Understanding the molecular pathogenesis of Huntington's disease is crucial for therapeutic development.
• Multiple cellular pathways are implicated in the neurodegenerative process of HD.
• Continued basic research is essential for discovering effective treatments to delay disease onset and progression.