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Fractionation for Resolution of Soluble and Insoluble Huntingtin Species
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Somatic CAG expansion in Huntington's disease is dependent on the MLH3 endonuclease domain, which can be excluded via

Jennie C L Roy1, Antonia Vitalo2,3, Marissa A Andrew2

  • 1Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.

Nucleic Acids Research
|March 22, 2021
PubMed

Insights

Targeting the MLH3 endonuclease domain significantly reduced CAG repeat expansion in Huntington

Area of Science:

  • Genetics
  • Molecular Biology
  • Neuroscience

Background:

  • Somatic CAG repeat expansion is a key driver of Huntington's disease (HD) pathogenesis.
  • The DNA mismatch repair pathway, particularly MLH3, influences somatic expansion in HD models.
  • Targeting factors that influence repeat expansion presents a therapeutic strategy for HD.

Purpose of the Study:

  • To investigate the role of the MLH3 endonuclease domain in somatic CAG expansion in HD.
  • To evaluate the therapeutic potential of targeting the MLH3 endonuclease domain for HD treatment.

Main Methods:

  • Utilized genetic approaches (point mutation) and pharmacological methods (splice switching oligonucleotides) in HD mouse models.
  • Assessed CAG expansion in brain and peripheral tissues of mice.
  • Examined CAG expansion in Huntington's disease patient-derived fibroblasts.

Main Results:

  • A point mutation in the MLH3 endonuclease domain abolished CAG expansion in HD mice.
  • Splice redirection to exclude the MLH3 endonuclease domain reduced somatic CAG expansion in mice.
  • Reduced CAG expansion was observed in HD patient fibroblasts by redirecting MLH3 splicing.

Conclusions:

  • The MLH3 endonuclease domain is a critical driver of somatic CAG expansion in Huntington's disease.
  • Targeting the MLH3 endonuclease domain offers a promising therapeutic strategy to slow disease progression in HD.
  • This therapeutic approach may also benefit other repeat expansion disorders.

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