Affordable Access

Publisher Website

Prevention of cytosolic IAPs degradation: a potential pharmacological target in Huntington's Disease

Authors
Journal
Pharmacological Research
1043-6618
Publisher
Elsevier
Publication Date
Volume
52
Issue
2
Identifiers
DOI: 10.1016/j.phrs.2005.01.006
Keywords
  • Huntington'S Disease
  • Iap
  • Htra2
  • Smac/Diablo
  • Mitochondria
Disciplines
  • Biology
  • Pharmacology

Abstract

Abstract Huntington'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 characterized by the presence of aggregates, 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-apoptotic factors, are aberrantly released from brain-derived cells expressing mutant huntingtin. This event causes a reduction in levels of the cytosolic IAP1 (Inhibitor of Apoptosis Protein-1) and XIAP (X-linked inhibitor apoptosis) antiapoptotic IAP family members. Reduced IAP levels are 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.

There are no comments yet on this publication. Be the first to share your thoughts.