Subtyping monogenic disorders: Huntington disease

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Huntington disease (HD) is a severe neurodegenerative disorder affecting psychiatric, cognitive, and motor functions.
• It stems from a genetic mutation in the huntingtin (HTT) gene, causing an expanded polyglutamine tract.
• The exact toxicity mechanism remains unclear, with current hypotheses focusing on mutant huntingtin (mHTT) aggregation.

Approach:

• This analysis reviews the current understanding of HD pathogenesis, including the role of HTT aggregation.
• It explores alternative hypotheses, such as the loss of wild-type HTT function.
• The study also considers the involvement of other biological pathways like autophagy and mitochondrial function.

Key Points:

• The expansion of polyglutamine repeats (>39) in the HTT gene is directly linked to Huntington disease.
• While mHTT aggregation is a hallmark, the reduction in wild-type HTT levels may also contribute to neurodegeneration.
• Aberrant pathways beyond HTT, including autophagic and mitochondrial dysfunction, contribute to HD's complexity.

Conclusions:

• The traditional 'one-gene, one-disease' model may be insufficient for Huntington disease.
• Identifying distinct HD subtypes based on altered biological pathways is crucial.
• Tailored therapeutic strategies targeting specific pathways, rather than solely HTT aggregation, are needed for effective HD treatment.