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Genotype-, aging-dependent abnormal caspase activity in Huntington disease blood cells

Ferdinando Squitieri1, Vittorio Maglione, Sara Orobello

  • 1Neurogenetics Unit and Rare Diseases Centre, IRCCS Neuromed, Pozzilli (IS), Italy. francesco.fornai@med.unipi.it

Journal of Neural Transmission (Vienna, Austria : 1996)
|April 27, 2011
PubMed

Insights

Huntington's Disease (HD) involves CAG repeat expansion in huntingtin (htt). This study reveals genotype-dependent caspase activity, reduced cell viability, and mitochondrial issues in HD patient blood cells, highlighting peripheral tissue relevance.

Area of Science:

  • Neuroscience
  • Genetics
  • Cell Biology

Background:

  • Huntington's Disease (HD) arises from CAG trinucleotide repeat expansions (>36) in the huntingtin (htt) gene.
  • The expanded polyglutamine (polyQ) tract in htt causes neuronal and peripheral tissue dysfunction.
  • Previous studies documented htt functions, but comprehensive caspase activity analysis in HD peripheral cells was limited.

Purpose of the Study:

  • To investigate genotype- and time-dependent caspase activity (caspase 2, 3, 6, 8, 9) in cultured blood cells from HD patients.
  • To assess cell viability and mitochondrial morphology alterations in relation to HD genotype.
  • To explore the role of peripheral tissues, like blood cells, as potential tools for HD research and biomarker discovery.

Main Methods:

  • Cultured blood cells from HD patients with varying CAG repeat sizes (homozygous, high-size heterozygous, low-size heterozygous) and controls were analyzed.
  • Caspa se activities (caspase 2, 3, 6, 8, 9) were measured.
  • Cell viability assays and mitochondrial morphology assessments were performed.
  • Cells were treated with cyanide to evaluate caspase responses.

Main Results:

  • Patients with homozygous or high-size heterozygous mutations (including Juvenile HD) showed significantly increased activities of caspases 2, 3, 6, 8, and 9.
  • These patients also exhibited decreased cell viability and pronounced mitochondrial morphological abnormalities compared to controls and low-mutation carriers.
  • Cyanide treatment exacerbated caspase activity, particularly in homozygous and high-expansion heterozygous cells, underscoring the role of caspase 8 and 9 as initiators in HD.
  • Age-dependent abnormalities in peripheral cells correlated with mutation toxicity, suggesting htt dosage or wild-type htt levels influence HD progression.

Conclusions:

  • Genotype and time significantly impact caspase activity, cell viability, and mitochondrial morphology in HD patient blood cells.
  • Peripheral blood cells offer a valuable model for studying HD pathogenesis and identifying potential biomarkers.
  • The findings suggest that mutated htt dosage or the absence of wild-type htt may be critical factors in HD clinical development and progression.

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