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

39824182
PMC11822645
Cell
Feb. 6, 2025
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02215, USA; Howard Hughes Medical Institute, Boston, MA 02215, USA. Electronic address: smccarro@broadinstitute.org.
Trinucleotide Repeat Expansion, Huntingtin Protein, Huntington Disease, Nerve Degeneration, Neurons, Mice, Animals, Male, Female, Humans, DNA Repeat Expansion
R01 HG006855
Berretta S, Goldman M, McCarroll SA, Mullally CD, Kohli R, Kashin S, McDonald TM, Handsaker RE, Lind G, Kamitaki N, Lawton E, Lee WS, Morris K, Reed NM, Ichihara K, Morakabati NR, Hogan M, Tan S
Handsaker RE, Kashin S, Reed NM, Tan S, Lee WS, McDonald TM, Morris K, Kamitaki N, Mullally CD, Morakabati NR, Goldman M, Lind G, Kohli R, Lawton E, Hogan M, Ichihara K, Berretta S, McCarroll SA. Long somatic DNA-repeat expansion drives neurodegeneration in Huntington's disease. Cell. 2025 Feb 6.

Abstract

In Huntington's disease (HD), striatal projection neurons (SPNs) degenerate during midlife; the core biological question involves how the disease-causing DNA repeat (CAG)n in the huntingtin (HTT) gene leads to neurodegeneration after decades of biological latency. We developed a single-cell method for measuring this repeat's length alongside genome-wide RNA expression. We found that the HTT CAG repeat expands somatically from 40-45 to 100-500+ CAGs in SPNs. Somatic expansion from 40 to 150 CAGs had no apparent cell-autonomous effect, but SPNs with 150-500+ CAGs lost positive and then negative features of neuronal identity, de-repressed senescence/apoptosis genes, and were lost. Our results suggest that somatic repeat expansion beyond 150 CAGs causes SPNs to degenerate quickly and asynchronously. We conclude that in HD, at any one time, most neurons have an innocuous but unstable HTT gene and that HD pathogenesis is a DNA process for almost all of a neuron's life.