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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis Regulatory Proteins
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Brain / metabolism
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Carrier Proteins / metabolism*
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Cell Line
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Cell Survival
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Cyclosporine / pharmacology
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Cytosol / metabolism
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High-Temperature Requirement A Serine Peptidase 2
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Humans
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Huntingtin Protein
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Huntington Disease / genetics
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Huntington Disease / metabolism*
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Inhibitor of Apoptosis Proteins
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Intracellular Signaling Peptides and Proteins
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Mice
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Mitochondria / metabolism
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Mitochondrial Proteins / metabolism*
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Mutation
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Proteins / metabolism*
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Pyrimidinones / pharmacology
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Serine Endopeptidases / metabolism*
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Thiones / pharmacology
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Ubiquitin-Protein Ligases
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X-Linked Inhibitor of Apoptosis Protein
Substances
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Apoptosis Regulatory Proteins
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Carrier Proteins
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DIABLO protein, human
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Diablo protein, mouse
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HTT protein, human
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Htt protein, mouse
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Huntingtin Protein
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Inhibitor of Apoptosis Proteins
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Intracellular Signaling Peptides and Proteins
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Mitochondrial Proteins
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Nerve Tissue Proteins
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Nuclear Proteins
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Proteins
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Pyrimidinones
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Thiones
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UCF 101
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X-Linked Inhibitor of Apoptosis Protein
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XIAP protein, human
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Cyclosporine
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BIRC2 protein, human
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Birc2 protein, mouse
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Ubiquitin-Protein Ligases
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Serine Endopeptidases
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HTRA2 protein, human
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High-Temperature Requirement A Serine Peptidase 2
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Htra2 protein, mouse