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

Robert E Handsaker; Seva Kashin; Nora M Reed; Steven Tan; Won-Seok Lee; Tara M McDonald; Kiely Morris; Nolan Kamitaki; Christopher D Mullally; Neda R Morakabati; Melissa Goldman; Gabriel Lind; Rhea Kohli; Elisabeth Lawton; Marina Hogan; Kiku Ichihara; Sabina Berretta; Steven A McCarroll

doi:10.1016/j.cell.2024.11.038

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

Cell. 2025 Jan 14:S0092-8674(24)01379-5. doi: 10.1016/j.cell.2024.11.038. Online ahead of print.

Authors

Robert E Handsaker¹, Seva Kashin², Nora M Reed³, Steven Tan³, Won-Seok Lee³, Tara M McDonald³, Kiely Morris⁴, Nolan Kamitaki³, Christopher D Mullally³, Neda R Morakabati⁴, Melissa Goldman³, Gabriel Lind³, Rhea Kohli³, Elisabeth Lawton⁴, Marina Hogan³, Kiku Ichihara³, Sabina Berretta⁵, Steven A McCarroll⁶

Affiliations

¹ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. Electronic address: [email protected].
² Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. Electronic address: [email protected].
³ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
⁴ McLean Hospital, Belmont, MA 02478, USA.
⁵ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; McLean Hospital, Belmont, MA 02478, USA; Department of Psychiatry, Harvard Medical School, Boston, MA 02215, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02215, USA. Electronic address: [email protected].
⁶ 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: [email protected].

PMID: 39824182
DOI: 10.1016/j.cell.2024.11.038

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.

Keywords: CAG; DNA repeats; Huntington’s disease; neurodegeneration; repeat instability; single-nucleus RNA-seq; somatic expansion; striatal projection neurons; triplet repeat disorders.