title: Noninvasive measurement of protein aggregation by mutant huntingtin fragments or alpha-synuclein in the lens.
abstract: Many diverse human diseases are associated with protein aggregation in ordered fibrillar structures called amyloid. Amyloid formation may mediate aberrant protein interactions that culminate in neurodegeneration in Alzheimer, Huntington, and Parkinson diseases and in prion encephalopathies. Studies of protein aggregation in the brain are hampered by limitations in imaging techniques and often require invasive methods that can only be performed postmortem. Here we describe transgenic mice in which aggregation-prone proteins that cause Huntington and Parkinson disease are expressed in the ocular lens. Expression of a mutant huntingtin fragment or alpha-synuclein in the lens leads to protein aggregation and cataract formation, which can be monitored in real time by noninvasive, highly sensitive optical techniques. Expression of a mutant huntingtin fragment in mice lacking the major lens chaperone, alphaB-crystallin, markedly accelerated the onset and severity of aggregation, demonstrating that the endogenous chaperone activity of alphaB-crystallin suppresses aggregation in vivo. These novel mouse models will facilitate the characterization of protein aggregation in vivo and are being used in efficient and economical screens for chemical and genetic modifiers of disease-relevant protein aggregation.
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, WA 98195, USA. pmuchowski@gladstone.ucsf.edu
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Muchowski
authors.forename: Richard
authors.initials: R
authors.lastname: Ramsden
authors.forename: QuangVu
authors.initials: Q
authors.lastname: Nguyen
authors.forename: Ernest E
authors.initials: EE
authors.lastname: Arnett
authors.forename: Teri M
authors.initials: TM
authors.lastname: Greiling
authors.forename: Susan K
authors.initials: SK
authors.lastname: Anderson
authors.forename: John I
authors.initials: JI
authors.lastname: Clark
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002386:Cataract / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D015870:Gene Expression; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007908:Lens, Crystalline / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D038203:alpha-Crystallin B Chain / Q000235:genetics / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D038203:alpha-Crystallin B Chain; D051844:alpha-Synuclein