caa a22 4500 445377844 CHVBK 20180317143008.0 cr unu---uuuuu 170323e20111101xx s 000 0 eng 10.1007/s00702-011-0646-1 doi (NATIONALLICENCE)springer-10.1007/s00702-011-0646-1 Genotype-, aging-dependent abnormal caspase activity in Huntington disease blood cells [Elektronische Daten] [Ferdinando Squitieri, Vittorio Maglione, Sara Orobello, Francesco Fornai] Huntington's Disease (HD) is caused by trinucleotide CAG repeat expansion >36 in huntingtin (htt), a protein with several documented functions. The elongated polyglutamine (polyQ) stretch in the N-terminal region of htt leads to dysfunctional and degenerative events in neurons and peripheral tissues. In this study, by extending the analysis to several caspase activities (i.e. caspase 2, 3, 6, 8 and 9), we describe genotype- and time- dependent caspase activity abnormalities, decreased cell viability and a large set of alterations in mitochondria morphology, in cultured blood cells from HD patients. Patients homozygous for CAG repeat mutations and heterozygous with high size mutations causing juvenile onset (JHD) presented significantly increased caspase 2, 3, 6, 8 and 9 activities, decreased cell viability and pronounced morphological abnormalities, compared with cells carrying low mutation size and controls. After cyanide treatment, all caspases increased their activities in homozygous and highly expanded heterozygous cells, caspase 8 and 9 increased also in those cells carrying low-size mutations, remarking their key role as ‘caspase initiators' in HD. The remarkable ageing-dependent abnormalities in peripheral cells carrying particularly toxic mutations (i.e. homozygotes' and JHD's blood cells) points out the potential dependence of clinical HD development and progression on either mutated htt dosage or missing wild type htt. Peripheral tissues (i.e. blood cells) may theoretically represent an important tool for studying HD mechanisms and searching for new biomarkers, according to the patients' genotype. Springer-Verlag, 2011 Caspase activities nationallicence Juvenile Huntington disease (JHD) nationallicence Homozygous CAG mutations nationallicence Abnormal mitochondria nationallicence Huntingtin (htt) dosage effect nationallicence Squitieri Ferdinando Neurogenetics Unit and Rare Diseases Centre, IRCCS Neuromed, Pozzilli (IS), Italy aut Maglione Vittorio Department of Pharmacology, University of Alberta, Edmonton, Canada aut Orobello Sara Neurogenetics Unit and Rare Diseases Centre, IRCCS Neuromed, Pozzilli (IS), Italy aut Fornai Francesco Department of Human Morphology and Applied Biology, University of Pisa, Via Roma 55, 56126, Pisa, Italy aut Journal of Neural Transmission Springer Vienna 118/11(2011-11-01), 1599-1607 0300-9564 118:11<1599 2011 118 702 https://doi.org/10.1007/s00702-011-0646-1 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s00702-011-0646-1 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Squitieri Ferdinando Neurogenetics Unit and Rare Diseases Centre, IRCCS Neuromed, Pozzilli (IS), Italy aut NATIONALLICENCE 700 1- Maglione Vittorio Department of Pharmacology, University of Alberta, Edmonton, Canada aut NATIONALLICENCE 700 1- Orobello Sara Neurogenetics Unit and Rare Diseases Centre, IRCCS Neuromed, Pozzilli (IS), Italy aut NATIONALLICENCE 700 1- Fornai Francesco Department of Human Morphology and Applied Biology, University of Pisa, Via Roma 55, 56126, Pisa, Italy aut NATIONALLICENCE 773 0- Journal of Neural Transmission Springer Vienna 118/11(2011-11-01), 1599-1607 0300-9564 118:11<1599 2011 118 702 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer