[Huntington disease. A review]

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder affecting motor, cognitive, and psychiatric functions.
• The disease is caused by an expanded CAG trinucleotide repeat in the huntingtin gene, leading to an abnormal huntingtin protein with an expanded polyglutamine (polyGln) stretch.
• The precise function of normal huntingtin and the exact pathogenic mechanisms of mutant huntingtin remain incompletely understood.

Purpose of the Study:

• To summarize the current understanding of Huntington's disease, including its genetic basis, molecular pathology, and clinical manifestations.
• To explore the potential roles of huntingtin protein in cellular functions and the proposed mechanisms of neurodegeneration in HD.
• To identify potential therapeutic strategies, such as the investigation of melatonin's properties.

Main Methods:

• Review of existing literature on Huntington's disease genetics, molecular mechanisms, and neuropathology.
• Analysis of the structural and functional consequences of the CAG/polyGln expansion in the huntingtin gene.
• Examination of proposed pathways contributing to neuronal dysfunction and death, including impaired energy metabolism and oxidative stress.

Main Results:

• The CAG/polyGln expansion in the huntingtin gene is the molecular hallmark of HD, with repeat lengths varying between normal individuals and patients.
• Mutant huntingtin is implicated in altered protein interactions, aggregate formation, impaired vesicular transport, and mitochondrial dysfunction.
• Neuropathological findings include significant atrophy of the striatum and frontal lobes, with specific neuronal populations being more vulnerable.

Conclusions:

• The neurodegeneration in HD likely results from a complex interplay of toxic gain-of-function mechanisms of mutant huntingtin, including proteolysis and altered protein interactions.
• Impaired cellular energy metabolism, oxidative stress, and excitotoxicity contribute to neuronal death.
• Further research into compounds like melatonin, with antioxidant properties, may offer potential therapeutic benefits for Huntington's disease.