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.
Rigamonti
D
D
Department of Pharmacological Sciences, University of Milano, Via Balzaretti 9, 20133 Milano, Italy.
Sipione
S
S
Goffredo
D
D
Zuccato
C
C
Fossale
E
E
Cattaneo
E
E
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