title: Genotype-, aging-dependent abnormal caspase activity in Huntington disease blood cells.
abstract: 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.
authors.affiliation: Neurogenetics Unit and Rare Diseases Centre, IRCCS Neuromed, Pozzilli (IS), Italy. francesco.fornai@med.unipi.it
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Squitieri
authors.forename: Vittorio
authors.initials: V
authors.lastname: Maglione
authors.forename: Sara
authors.initials: S
authors.lastname: Orobello
authors.forename: Francesco
authors.initials: F
authors.lastname: Fornai
mesh_terms: D000368:Aged; D000375:Aging / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D020169:Caspases / Q000097:blood*; D002648:Child; D004789:Enzyme Activation / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D007962:Leukocytes / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D061251:Primary Cell Culture; D055815:Young Adult
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D020169:Caspases