title: Integration-independent Transgenic Huntington Disease Fragment Mouse Models Reveal Distinct Phenotypes and Life Span in Vivo.
abstract: The cascade of events that lead to cognitive decline, motor deficits, and psychiatric symptoms in patients with Huntington disease (HD) is triggered by a polyglutamine expansion in the N-terminal region of the huntingtin (HTT) protein. A significant mechanism in HD is the generation of mutant HTT fragments, which are generally more toxic than the full-length HTT. The protein fragments observed in human HD tissue and mouse models of HD are formed by proteolysis or aberrant splicing of HTT. To systematically investigate the relative contribution of the various HTT protein proteolysis events observed in vivo, we generated transgenic mouse models of HD representing five distinct proteolysis fragments ending at amino acids 171, 463, 536, 552, and 586 with a polyglutamine length of 148. All lines contain a single integration at the ROSA26 locus, with expression of the fragments driven by the chicken β-actin promoter at nearly identical levels. The transgenic mice N171-Q148 and N552-Q148 display significantly accelerated phenotypes and a shortened life span when compared with N463-Q148, N536-Q148, and N586-Q148 transgenic mice. We hypothesized that the accelerated phenotype was due to altered HTT protein interactions/complexes that accumulate with age. We found evidence for altered HTT complexes in caspase-2 fragment transgenic mice (N552-Q148) and a stronger interaction with the endogenous HTT protein. These findings correlate with an altered HTT molecular complex and distinct proteins in the HTT interactome set identified by mass spectrometry. In particular, we identified HSP90AA1 (HSP86) as a potential modulator of the distinct neurotoxicity of the caspase-2 fragment mice (N552-Q148) when compared with the caspase-6 transgenic mice (N586-Q148).
authors.affiliation: From the Buck Institute for Research on Aging, Novato, California 94945.
authors.forename: Robert
authors.initials: R
authors.lastname: O'Brien
authors.affiliation: From the Buck Institute for Research on Aging, Novato, California 94945.
authors.forename: Francesco
authors.initials: F
authors.lastname: DeGiacomo
authors.affiliation: From the Buck Institute for Research on Aging, Novato, California 94945.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Holcomb
authors.affiliation: From the Buck Institute for Research on Aging, Novato, California 94945.
authors.forename: Akilah
authors.initials: A
authors.lastname: Bonner
authors.affiliation: From the Buck Institute for Research on Aging, Novato, California 94945.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Ring
authors.affiliation: From the Buck Institute for Research on Aging, Novato, California 94945.
authors.forename: Ningzhe
authors.initials: N
authors.lastname: Zhang
authors.affiliation: From the Buck Institute for Research on Aging, Novato, California 94945.
authors.forename: Khan
authors.initials: K
authors.lastname: Zafar
authors.affiliation: Evotec AG, Manfred Eigen Campus, Essener Bogen 7, 22419 Hamburg, Germany, and.
authors.forename: Andreas
authors.initials: A
authors.lastname: Weiss
authors.affiliation: CHDI Management/CHDI Foundation, Inc., Princeton, New Jersey 08540.
authors.forename: Brenda
authors.initials: B
authors.lastname: Lager
authors.affiliation: From the Buck Institute for Research on Aging, Novato, California 94945.
authors.forename: Birgit
authors.initials: B
authors.lastname: Schilling
authors.affiliation: From the Buck Institute for Research on Aging, Novato, California 94945.
authors.forename: Bradford W
authors.initials: BW
authors.lastname: Gibson
authors.affiliation: From the Buck Institute for Research on Aging, Novato, California 94945.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Chen
authors.affiliation: CHDI Management/CHDI Foundation, Inc., Princeton, New Jersey 08540.
authors.forename: Seung
authors.initials: S
authors.lastname: Kwak
authors.affiliation: From the Buck Institute for Research on Aging, Novato, California 94945, lellerby@buckinstitute.org.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Ellerby
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology; D018389:Codon, Nonsense; D004195:Disease Models, Animal; D005260:Female; D057809:HEK293 Cells; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000503:physiopathology; D008136:Longevity; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D025941:Protein Interaction Mapping; D059748:Proteolysis
chemical_list: D018389:Codon, Nonsense; D018841:HSP90 Heat-Shock Proteins; C086055:HTT protein, human; C500524:Hsp86 protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins
keywords: caspase; neurodegenerative disease; polyglutamine disease; proteolysis; transgenic mice