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Errors in the Huntington’s disease gene accumulate slowly and then all at once

Inherited repeat mutations in the HTT gene expand in neurons over decades before crossing a toxic threshold, revealing a long time window for therapy.
By
  1. Veera M. Rajagopal

    1. Veera M. Rajagopal is at the Regeneron Genetics Center, Tarrytown, New York 10591, USA.

  2. Sahar Gelfman

    1. Sahar Gelfman is at the Regeneron Genetics Center, Tarrytown, New York 10591, USA.

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Huntington’s disease, a neurodegenerative condition, stems from a mutation in the HTT gene sequence in which a trio of nucleotides, cytosine, adenine and guanine (referred to as CAG), becomes repeated to abnormal lengths. HTT codes for the protein huntingtin, which is abundant in the brain but has a poorly understood function. Despite three decades of research since its discovery, the mechanism linking HTT mutations to Huntington’s disease remains unclear. Writing in Cell, Handsaker et al.1 report single-cell analyses suggesting that neuronal toxicity emerges only after decades of CAG-repeat expansions in HTT, potentially offering a wide therapeutic window.

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Nature 639, 584-586 (2025)

doi: https://doi.org/10.1038/d41586-025-00717-9

References

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Competing Interests

V.M.R. and S.G. are full-time employees of Regeneron Genetics Center, a fully owned subsidiary of Regeneron Pharmaceuticals Inc.

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