PolyQ length-dependent metabolic alterations and DNA damage drive human astrocyte dysfunction in Huntington's disease

Area of Science:

• Neuroscience
• Genetics
• Cell Biology

Background:

• Huntington's Disease (HD) is a neurodegenerative disorder linked to polyglutamine (polyQ) expansion in the Huntingtin gene.
• Astrocyte dysfunction is implicated in HD pathogenesis, but the underlying molecular mechanisms remain unclear.

Purpose of the Study:

• To investigate polyglutamine (polyQ) length-dependent molecular and functional changes in astrocytes from patients with Huntington's Disease (HD).
• To identify key pathways contributing to astrocyte dysfunction in HD.

Main Methods:

• Transcriptomic analysis of patient-derived pluripotent stem cell (PSC)-derived astrocyte lines.
• Weighted gene co-expression network analysis (WGCNA) comparing astrocyte data with post-mortem HD cohorts.
• Assessment of astrocyte reactivity, metabolic activity, metabolite release, DNA damage, and DNA damage response.

Main Results:

• Astrocytes with similar polyQ lengths exhibited shared differentially expressed genes (DEGs).
• Gene expression related to astrocyte reactivity and metabolism was polyQ length-dependent, with hypermetabolism in shorter polyQ lengths and reduced activity/metabolite release in longer polyQ lengths.
• All HD astrocytes displayed increased DNA damage, DNA damage response, and upregulation of mismatch repair genes.

Conclusions:

• This study demonstrates polyQ length-dependent phenotypes and functional alterations in HD astrocytes for the first time.
• Increased DNA damage and DNA damage response are identified as potential contributors to HD astrocyte dysfunction.