Long somatic DNA-repeat expansion drives neurodegeneration in Huntington's disease

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Huntington's disease (HD) is characterized by the degeneration of striatal projection neurons (SPNs) in midlife.
• The underlying cause is the expansion of the (CAG)n repeat in the huntingtin (HTT) gene, but the mechanism of late-onset neurodegeneration remains unclear.

Purpose of the Study:

• To investigate the role of somatic HTT CAG repeat expansion in SPN degeneration in Huntington's disease.
• To correlate HTT CAG repeat length with genome-wide RNA expression and neuronal cell fate.

Main Methods:

• Development of a single-cell method to measure HTT CAG repeat length and genome-wide RNA expression simultaneously.
• Analysis of somatic repeat expansion in SPNs from individuals with Huntington's disease.

Main Results:

• Somatic expansion of the HTT CAG repeat occurs in SPNs, ranging from 40-45 to over 500 repeats.
• Expansion to 150 CAGs had no discernible cell-autonomous effect.
• SPNs with 150-500+ CAGs exhibited loss of neuronal identity markers, de-repression of senescence/apoptosis genes, and subsequent cell loss.

Conclusions:

• Somatic HTT CAG repeat expansion beyond 150 repeats triggers rapid and asynchronous SPN degeneration in Huntington's disease.
• HD pathogenesis is primarily a DNA-driven process throughout most of a neuron's lifespan.
• Most neurons in HD patients may harbor an unstable but initially innocuous HTT gene.