ucf-101 and Huntington-Disease

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.

Topics: Animals; Apoptosis Regulatory Proteins; Brain; Carrier Proteins; Cell Line; Cell Survival; Cyclosporine; Cytosol; High-Temperature Requirement A Serine Peptidase 2; Humans; Huntingtin Protein; Huntington Disease; Inhibitor of Apoptosis Proteins; Intracellular Signaling Peptides and Proteins; Mice; Mitochondria; Mitochondrial Proteins; Mutation; Nerve Tissue Proteins; Nuclear Proteins; Proteins; Pyrimidinones; Serine Endopeptidases; Thiones; Ubiquitin-Protein Ligases; X-Linked Inhibitor of Apoptosis Protein