Huntingtin's neuroprotective activity occurs via inhibition of procaspase-9 processing.
Huntington's Disease is an inherited neurodegenerative disease that affects the medium spiny neurons in the striatum. The disease is caused by the expansion of a polyglutamine sequence in the N terminus of Huntingtin (Htt), a widely expressed protein. Recently, we have found that Htt is an antiapoptotic protein in striatal cells and acts by preventing caspase-3 activity. Here we report that Htt overexpression in other CNS-derived cells can protect them from more than 20 days exposure to fatal stimuli. In particular, we found that cytochrome c continues to be released from mitochondria into the cytosol of cells that overexpress normal Htt. However, procaspase-9 is not processed, indicating that wild-type Htt (wtHtt) acts downstream of cytochrome c release. These data show that Htt inhibits neuronal cell death by interfering with the activity of the apoptosome complex.
Department of Pharmacological Sciences, University of Milano, Via Balzaretti 9, 20133 Milano, Italy.
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Rigamonti
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Sipione
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Goffredo
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Zuccato
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Fossale
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Cattaneo
D017209:Apoptosis / Q000502:physiology; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002461:Cell Line, Transformed; D003574:Cytochrome c Group / Q000378:metabolism; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D008928:Mitochondria / Q000201:enzymology; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009687:Nuclear Proteins / Q000502:physiology*
D061945:Caspase Inhibitors; D003574:Cytochrome c Group; D004792:Enzyme Precursors; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C506433:CASP9 protein, human; D053453:Caspase 9; D020169:Caspases