title: Transgenic mice expressing caspase-6-derived N-terminal fragments of mutant huntingtin develop neurologic abnormalities with predominant cytoplasmic inclusion pathology composed largely of a smaller proteolytic derivative.
abstract: Recent studies have implicated an N-terminal caspase-6 cleavage product of mutant huntingtin (htt) as an important mediator of toxicity in Huntington's disease (HD). To directly assess the consequences of such fragments on neurologic function, we produced transgenic mice that express a caspase-6 length N-terminal fragment of mutant htt (N586) with both normal (23Q) and disease (82Q) length glutamine repeats. In contrast to mice expressing N586-23Q, mice expressing N586-82Q accumulate large cytoplasmic inclusion bodies that can be visualized with antibodies to epitopes throughout the N586 protein. However, biochemical analyses of aggregated mutant huntingtin in these mice demonstrated that the inclusion bodies are composed largely of a much smaller htt fragment (terminating before residue 115), with lesser amounts of full-length N586-82Q fragments. Mice expressing the N586-82Q fragment show symptoms typical of previously generated mice expressing mutant huntingtin fragments, including failure to maintain weight, small brain weight and reductions in specific mRNAs in the striatum. Uniquely, these N586-82Q mice develop a progressive movement disorder that includes dramatic deficits in motor performance on the rotarod and ataxia. Our findings suggest that caspase-6-derived fragments of mutant htt are capable of inducing novel HD-related phenotypes, but these fragments are not terminal cleavage products as they are subject to further proteolysis. In this scenario, mutant htt fragments derived from caspase 6, or possibly other proteases, could mediate HD pathogenesis via a 'hit and run' type of mechanism in which caspase-6, or other larger N-terminal fragments, mediate a neurotoxic process before being cleaved to a smaller fragment that accumulates pathologically.
authors.affiliation: Department of Neuroscience and Santa Fe Health Alzheimer’s Disease Research Center, McKnight Brain Institute, University of Florida, 100 Newell Dr., Gainesville, FL 32610, USA.
authors.forename: Andrew T N
authors.initials: AT
authors.lastname: Tebbenkamp
authors.forename: Cameron
authors.initials: C
authors.lastname: Green
authors.forename: Guilian
authors.initials: G
authors.lastname: Xu
authors.forename: Eileen M
authors.initials: EM
authors.lastname: Denovan-Wright
authors.forename: Aaron C
authors.initials: AC
authors.lastname: Rising
authors.forename: Susan E
authors.initials: SE
authors.lastname: Fromholt
authors.forename: Hilda H
authors.initials: HH
authors.lastname: Brown
authors.forename: Debbie
authors.initials: D
authors.lastname: Swing
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Mandel
authors.forename: Lino
authors.initials: L
authors.lastname: Tessarollo
authors.forename: David R
authors.initials: DR
authors.lastname: Borchelt
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001259:Ataxia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053178:Caspase 6; D003342:Corpus Striatum / Q000378:metabolism* / Q000473:pathology; D015870:Gene Expression; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002479:Inclusion Bodies / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D045442:Rotarod Performance Test
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; C505514:CASP6 protein, human; D053178:Caspase 6