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

In Huntington's disease (HD), striatal projection neurons (SPNs) degenerate during midlife; the core biological question involves how the disease-causing DNA repeat (CAG)<sub>n</sub> 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.

Authors

Institutions

Publication Details

Journal
Cell
Published
2025-01-16
DOI
https://doi.org/10.1016/j.cell.2024.11.038
Citations
138
Primary Topic
Genetic Neurodegenerative Diseases
Type
article
Field-Weighted Citation Impact
123.64
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

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

Seva Kashin, Sabina Berretta, Nolan Kamitaki, Rhea Kohli et al.
138 citations
Cell
Genetic Neurodegenerative Diseases
123.64
article

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

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

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)<sub>n</sub> 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.

CellVol. 188(3)
Broad Institute (US), McLean Hospital (US)
Openalex Percentile: Top 0%
Genetic Neurodegenerative Diseases
123.64
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.