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Suppression of aggregate formation of mutant huntingtin potentiates CREB-binding protein sequestration and apoptotic

Yong-Joon Choi1, Song-In Kim, Jae-Won Lee

  • 1Department of Pharmacology, College of Medicine, Kangwon National University, Chuncheon, South Korea.

Molecular and Cellular Neurosciences
|November 30, 2011
PubMed

Insights

Mutant huntingtin aggregates are hallmarks of Huntington's disease (HD), but non-aggregate forms may also drive pathogenesis. This study reveals that even non-aggregated mutant huntingtin can sequester CBP, leading to apoptosis and decreased PGC1-α expression in HD.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Huntington's disease (HD) is characterized by mutant huntingtin aggregates.
  • The role of these aggregates and mutant huntingtin in HD pathogenesis is not fully understood.
  • Sequestration of CBP by mutant huntingtin is implicated in HD, but the necessity of aggregate formation for this process is unclear.

Purpose of the Study:

  • To investigate whether mutant huntingtin aggregate formation is essential for CBP sequestration and subsequent pathogenic events in HD.
  • To explore the pathogenic role of non-aggregate forms of mutant huntingtin.

Main Methods:

  • Engineered N-terminal and C-terminal YFP-tagged exon 1 huntingtin constructs to modulate aggregation propensity.
  • Assessed aggregation frequency, CBP sequestration, apoptosis, and gene expression changes (microarray, PGC1-α levels).

Main Results:

  • C-terminally tagged huntingtin (MT-YFP) showed efficient aggregation.
  • N-terminally tagged huntingtin (YFP-MT) exhibited significantly reduced aggregation but increased CBP sequestration and apoptosis.
  • Microarray analysis revealed transcriptional changes favoring apoptosis.
  • PGC1-α expression was significantly decreased in YFP-MT.

Conclusions:

  • Microscopically non-aggregate forms of mutant huntingtin can exert essential pathogenic roles in Huntington's disease.
  • Aggregate formation may not be strictly necessary for all pathogenic mechanisms of mutant huntingtin, such as CBP sequestration and apoptosis induction.

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