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

"Huntington Disease (HD) is a fatal genetic brain disorder in which most of a person’s striatal projection neurons (SPNs) degenerate and die. Science has long sought to understand why SPNs are so vulnerable in HD, why this pathology follows decades of apparent health, and how the disease-causing inherited DNA repeat (CAGn, n > 36) in the huntingtin (HTT) gene leads to this neurodegeneration. This DNA repeat exhibits somatic mosaicism (variable length); we developed a way to measure its length together with genome-wide RNA expression in the same individual cells. We found that, in persons with typical inherited HD-causing alleles (of < 50 CAG repeats), the CAG-repeat tract routinely expanded to 100-500+ CAG repeats in SPNs but rarely if ever did so in striatal interneurons or glia. Surprisingly, gene expression in these persons’ individual SPNs exhibited no apparent relationship to those SPNs’ CAG-repeat lengths across a wide range (36-150 repeats). In contrast, sparse SPNs with longer (150-500+) CAG repeats had profound gene-expression distortions which affected hundreds of genes, escalated alongside further repeat expansion, and culminated in widespread gene de-repression and expression of senescence/apoptosis genes. Our experiments, analyses, and simulations suggest that individual SPNs undergo decades of biologically quiet DNA repeat expansion, then asynchronously enter a brief toxicity phase before dying. We conclude that, at any moment in time, most SPNs in persons with HD actually have a benign (but somewhat unstable) huntingtin gene; and that HD is a DNA process for almost all of a neuron’s life."

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