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Golgi protein ACBD3 mediates neurotoxicity associated with Huntington's disease

Juan I Sbodio1, Bindu D Paul, Carolyn E Machamer

  • 1The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, Baltimore, MD 21205, USA.

Cell Reports
|September 10, 2013
PubMed

Insights

Huntington's disease neurodegeneration involves the protein ACBD3. This Golgi protein mediates mutant huntingtin toxicity, offering new therapeutic targets for this devastating brain disorder.

Area of Science:

  • Neuroscience
  • Genetics
  • Molecular Biology

Background:

  • Huntington's disease (HD) is an inherited neurodegenerative disorder.
  • It is caused by expanded polyglutamine repeats in the huntingtin gene.
  • Selective degeneration of the corpus striatum occurs despite widespread mutant huntingtin expression.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying striatal selectivity in Huntington's disease.
  • To identify key proteins mediating mutant huntingtin (mHtt) cytotoxicity in the striatum.

Main Methods:

  • Investigated the role of the Golgi protein acyl-CoA binding domain containing 3 (ACBD3).
  • Examined the formation of a Rhes/mHtt/ACBD3 complex.
  • Assessed ACBD3 levels in HD patient samples, cell lines, and mouse models.

Main Results:

  • ACBD3 levels are significantly elevated in the striatum of HD patients and models.
  • ACBD3 mediates mHtt-induced cytotoxicity through a Rhes/mHtt/ACBD3 complex.
  • ACBD3 deletion prevents HD neurotoxicity, while overexpression exacerbates it.

Conclusions:

  • ACBD3 is a critical mediator of neurodegeneration in Huntington's disease.
  • Elevated ACBD3 levels, potentially due to cellular stresses, contribute to HD pathogenesis.
  • Targeting the Rhes/mHtt/ACBD3 interaction presents a potential therapeutic strategy for HD.

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