title: Specific caspase interactions and amplification are involved in selective neuronal vulnerability in Huntington's disease.
abstract: Huntington's disease (HD) is an autosomal dominant progressive neurodegenerative disorder resulting in selective neuronal loss and dysfunction in the striatum and cortex. The molecular pathways leading to the selectivity of neuronal cell death in HD are poorly understood. Proteolytic processing of full-length mutant huntingtin (Htt) and subsequent events may play an important role in the selective neuronal cell death found in this disease. Despite the identification of Htt as a substrate for caspases, it is not known which caspase(s) cleaves Htt in vivo or whether regional expression of caspases contribute to selective neuronal cells loss. Here, we evaluate whether specific caspases are involved in cell death induced by mutant Htt and if this correlates with our recent finding that Htt is cleaved in vivo at the caspase consensus site 552. We find that caspase-2 cleaves Htt selectively at amino acid 552. Further, Htt recruits caspase-2 into an apoptosome-like complex. Binding of caspase-2 to Htt is polyglutamine repeat-length dependent, and therefore may serve as a critical initiation step in HD cell death. This hypothesis is supported by the requirement of caspase-2 for the death of mouse primary striatal cells derived from HD transgenic mice expressing full-length Htt (YAC72). Expression of catalytically inactive (dominant-negative) forms of caspase-2, caspase-7, and to some extent caspase-6, reduced the cell death of YAC72 primary striatal cells, while the catalytically inactive forms of caspase-3, -8, and -9 did not. Histological analysis of post-mortem human brain tissue and YAC72 mice revealed activation of caspases and enhanced caspase-2 immunoreactivity in medium spiny neurons of the striatum and the cortical projection neurons when compared to controls. Further, upregulation of caspase-2 correlates directly with decreased levels of brain-derived neurotrophic factor in the cortex and striatum of 3-month YAC72 transgenic mice and therefore suggests that these changes are early events in HD pathogenesis. These data support the involvement of caspase-2 in the selective neuronal cell death associated with HD in the striatum and cortex.
authors.affiliation: The Buck Institute for Age Research, Novato, CA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Hermel
authors.forename: J
authors.initials: J
authors.lastname: Gafni
authors.forename: S S
authors.initials: SS
authors.lastname: Propp
authors.forename: B R
authors.initials: BR
authors.lastname: Leavitt
authors.forename: C L
authors.initials: CL
authors.lastname: Wellington
authors.forename: J E
authors.initials: JE
authors.lastname: Young
authors.forename: A S
authors.initials: AS
authors.lastname: Hackam
authors.forename: A V
authors.initials: AV
authors.lastname: Logvinova
authors.forename: A L
authors.initials: AL
authors.lastname: Peel
authors.forename: S F
authors.initials: SF
authors.lastname: Chen
authors.forename: V
authors.initials: V
authors.lastname: Hook
authors.forename: R
authors.initials: R
authors.lastname: Singaraja
authors.forename: S
authors.initials: S
authors.lastname: Krajewski
authors.forename: P C
authors.initials: PC
authors.lastname: Goldsmith
authors.forename: H M
authors.initials: HM
authors.lastname: Ellerby
authors.forename: M R
authors.initials: MR
authors.lastname: Hayden
authors.forename: D E
authors.initials: DE
authors.lastname: Bredesen
authors.forename: L M
authors.initials: LM
authors.lastname: Ellerby
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D053143:Caspase 2; D053148:Caspase 3; D053178:Caspase 6; D053179:Caspase 7; D020169:Caspases / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology; D002540:Cerebral Cortex / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C505407:CASP3 protein, human; C505514:CASP6 protein, human; C505520:CASP7 protein, human; C505409:Casp3 protein, mouse; C505516:Casp6 protein, mouse; C505524:Casp7 protein, mouse; D053143:Caspase 2; D053148:Caspase 3; D053178:Caspase 6; D053179:Caspase 7; D020169:Caspases