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Transposable element activation promotes neurodegeneration in a Drosophila model of Huntington's disease

Assunta Maria Casale1, Francesco Liguori1, Federico Ansaloni2

  • 1Department of Biology and Biotechnology "C. Darwin", Sapienza University of Rome, Rome, Italy.

Iscience
|January 17, 2022
PubMed

Insights

This study reveals that increased transposable element (TE) activity contributes to neurotoxicity in Huntington's disease (HD) models. Inhibiting TE mobilization offers a promising therapeutic strategy for this genetic disorder.

Area of Science:

  • Neuroscience
  • Genetics
  • Molecular Biology

Background:

  • Huntington's disease (HD) is a fatal neurodegenerative disorder caused by CAG repeat expansion in the Huntingtin gene.
  • Currently, no effective treatments exist for HD, necessitating the identification of novel therapeutic targets.
  • Transposable elements (TEs), or 'jumping genes,' are DNA sequences capable of changing their genomic position and are implicated in neurological diseases.

Purpose of the Study:

  • To investigate the role of TE activity in Huntington's disease pathogenesis.
  • To explore the potential of inhibiting TE mobilization as a therapeutic strategy for HD.

Main Methods:

  • Utilized a *Drosophila melanogaster* model of Huntington's disease.
  • Assessed TE expression and mobilization in the HD model.
  • Administered Reverse Transcriptase inhibitors to block TE mobilization.
  • Evaluated the effects of TE inhibition on neurodegeneration, genome instability, and lifespan.

Main Results:

  • TE expression and mobilization were significantly increased in the *Drosophila* HD model.
  • Inhibition of TE mobilization using Reverse Transcriptase inhibitors rescued polyglutamine-dependent eye neurodegeneration.
  • TE inhibition also reduced genome instability in larval brains and extended fly lifespan.
  • These findings demonstrate a link between TE activation and polyQ-induced neurotoxicity.

Conclusions:

  • TE activation is implicated in the neurotoxicity associated with Huntington's disease.
  • Inhibiting TE mobilization presents a potential novel therapeutic avenue for treating HD.
  • Targeting TE activity could offer a new strategy to combat polyglutamine-induced neurodegeneration.

Keywords:
Biological sciencesMolecular biologyNeuroscience

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