Hunting,ton's Disease (HD) is a neurodegenerative disorder caused by an abnormally expanded polyglutamine trait in the amino-terminal region of huntingtin. Pathogenic mechanisms involve a gained toxicity of mutant huntingtin and a potentially reduced neuroprotective function of the wild-type allele. Among the molecular abnormalities reported, HD cells are characterised by the presence of aggregate. transcriptional dysregulation, altered mitochondrial membrane potential and aberrant Ca++ handling. In addition, upon exposure to toxic stimuli. increased mitochondrial release of cytochrome C and activation of caspase-9 and caspase-3 are found in HD cells and tissue. Here we report that HTRA2 and Smac/DIABLO, two additional mitochondrial pro-apoptootic factors. are aberrantly released from brain-derived cells expressing mutant huntingtin, This event causes a reduction in levels of the cytostrlic IAP1 (Inhibitor of Apoptosis Protein-1) and XIAP (X-linked inhibitor apoptosis) antiapoptotic IAP family members. Reduced IAP levels arc also found in post-mortem [HD) brain tissue. Treatment with ucf101, a serine protease HTRA2 specific inhibitor. counteracts IAPs degradation in HD cells and increases their survival. These results point to the IAPs as potential pharmacological targets in Huntington's Disease. (c) 2005 Elsevier Ltd. All rights reserved.
Prevention of cytosolic IAPs degradation: a potential pharmacological target in Huntington's Disease / D. Goffredo, D. Rigamonti, C. Zuccato, M. Tartari, M. Valenza, E. Cattaneo. - In: PHARMACOLOGICAL RESEARCH. - ISSN 1043-6618. - 52:2(2005), pp. 140-150.
|Titolo:||Prevention of cytosolic IAPs degradation: a potential pharmacological target in Huntington's Disease|
GOFFREDO, DONATO (Primo)
RIGAMONTI, DOROTEA (Secondo)
VALENZA, MARTA (Penultimo)
CATTANEO, ELENA (Ultimo)
|Parole Chiave:||HTRA2; Huntington's disease; IAP; Mitochondria; Smac/DIABLO|
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
|Data di pubblicazione:||2005|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1016/j.phrs.2005.01.006|
|Appare nelle tipologie:||01 - Articolo su periodico|