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Pathogenic mechanisms
A15 Genotype and ageing dependent mitochondrial abnormalities and increased caspase activities in Huntington's disease lymphoblasts
  1. V Maglione,
  2. E Amico,
  3. F Squitieri
  1. Neurogenetics and Rare Disease Centre, IRCCS Neuromed, Pozzilli, Italy


Background Expanded huntingtin causes brain and peripheral cell dysfunction. In lymphoblasts carrying highly expanded mutations, an increase in caspase 3 and 9 was described, as well as an increase in caspase 3 and 8 activities in cells with homozygous CAG mutation compared with heterozygotes and controls. Additionally, aberrant mitochondria morphology in peripheral cells from HD homozygous patients was also described. Coherently, patients carrying homozygous and highly expanded mutations show a particularly severe clinical course.

Aim We simulated disease progression by investigating the time dependent ultrastructural and biochemical (extended caspase activities) alterations in lymphoblasts from HD homozygotes for mutation (homoHD), JHD with long mutation sizes (highHD), adult HD with low penetrance mutation (lowHD) patients and controls (ctrls).

Results Cyanide (CN) induced caspase 2, 3 and 6 activities increased in both homoHD and highHD compared with lowHD and ctrls, analysed by colorimetric assays. Caspase 8 and 9 activities increased in all HD cell lines. Protease activities changed over time in cells cultured for 6 months with a significant increase in highHD and homoHD. Electron microscopy analysis showed an increased area and an aberrant perinuclear clustering of mitochondria in highHD cell lines, potentially correlated with the altered protease activities. Conversely, homozygous cell lines showed a significant increase in mitochondrial area already under basal conditions without any increase over the time.

Conclusion We describe ageing related biochemical and ultrastructural changes in HD peripheral cells, potentially reflecting the brain pathology, in a time related dose dependent manner. By our approach, we remark potentiality for searching novel HD biomarkers.

  • ageing in Huntington disease
  • caspase activity
  • electron microscopy
  • mitochondrial morphology

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