Huntington disease: new insights into molecular pathogenesis and therapeutic opportunities

Nat Rev Neurol. 2020 Oct;16(10):529-546. doi: 10.1038/s41582-020-0389-4. Epub 2020 Aug 14.


Huntington disease (HD) is a neurodegenerative disease caused by CAG repeat expansion in the huntingtin gene (HTT) and involves a complex web of pathogenic mechanisms. Mutant HTT (mHTT) disrupts transcription, interferes with immune and mitochondrial function, and is aberrantly modified post-translationally. Evidence suggests that the mHTT RNA is toxic, and at the DNA level, somatic CAG repeat expansion in vulnerable cells influences the disease course. Genome-wide association studies have identified DNA repair pathways as modifiers of somatic instability and disease course in HD and other repeat expansion diseases. In animal models of HD, nucleocytoplasmic transport is disrupted and its restoration is neuroprotective. Novel cerebrospinal fluid (CSF) and plasma biomarkers are among the earliest detectable changes in individuals with premanifest HD and have the sensitivity to detect therapeutic benefit. Therapeutically, the first human trial of an HTT-lowering antisense oligonucleotide successfully, and safely, reduced the CSF concentration of mHTT in individuals with HD. A larger trial, powered to detect clinical efficacy, is underway, along with trials of other HTT-lowering approaches. In this Review, we discuss new insights into the molecular pathogenesis of HD and future therapeutic strategies, including the modulation of DNA repair and targeting the DNA mutation itself.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Biomarkers / blood
  • Biomarkers / cerebrospinal fluid
  • Clinical Trials as Topic / methods
  • DNA Repair / genetics
  • Genetic Therapy / methods
  • Genetic Therapy / trends
  • Genome-Wide Association Study / methods
  • Genome-Wide Association Study / trends*
  • Humans
  • Huntingtin Protein / genetics*
  • Huntington Disease / diagnosis
  • Huntington Disease / genetics*
  • Huntington Disease / metabolism
  • Huntington Disease / therapy*
  • Mutation / genetics*


  • Biomarkers
  • Huntingtin Protein