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

IF 45.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Pub Date : 2025-01-16 DOI:10.1016/j.cell.2024.11.038

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

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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.

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来源期刊

Cell 生物-生化与分子生物学

CiteScore

110.00

自引率

0.80%

发文量

396

审稿时长

2 months

期刊介绍： Cells is an international, peer-reviewed, open access journal that focuses on cell biology, molecular biology, and biophysics. It is affiliated with several societies, including the Spanish Society for Biochemistry and Molecular Biology (SEBBM), Nordic Autophagy Society (NAS), Spanish Society of Hematology and Hemotherapy (SEHH), and Society for Regenerative Medicine (Russian Federation) (RPO). The journal publishes research findings of significant importance in various areas of experimental biology, such as cell biology, molecular biology, neuroscience, immunology, virology, microbiology, cancer, human genetics, systems biology, signaling, and disease mechanisms and therapeutics. The primary criterion for considering papers is whether the results contribute to significant conceptual advances or raise thought-provoking questions and hypotheses related to interesting and important biological inquiries. In addition to primary research articles presented in four formats, Cells also features review and opinion articles in its "leading edge" section, discussing recent research advancements and topics of interest to its wide readership.