title: Early phenotypes that presage late-onset neurodegenerative disease allow testing of modifiers in Hdh CAG knock-in mice.
abstract: In Huntington's disease (HD), CAG repeats extend a glutamine tract in huntingtin to initiate the dominant loss of striatal neurons and chorea. Neuropathological changes include the formation of insoluble mutant N-terminal fragment, as nuclear/neuropil inclusions and filter-trap amyloid, which may either participate in the disease process or be a degradative by-product. In young Hdh knock-in mice, CAGs that expand the glutamine tract in mouse huntingtin to childhood-onset HD lengths lead to nuclear accumulation of full-length mutant huntingtin and later accumulation of insoluble fragment. Here we report late-onset neurodegeneration and gait deficits in older Hdh(Q111) knock-in mice, demonstrating that the nuclear phenotypes comprise early stages in a disease process that conforms to genetic and pathologic criteria determined in HD patients. Furthermore, using the early nuclear-accumulation phenotypes as surrogate markers, we show in genetic experiments that the disease process, initiated by full-length mutant protein, is hastened by co-expression of mutant fragment; therefore, accrual of insoluble-product in already compromised neurons may exacerbate pathogenesis. In contrast, timing of early disease events was not altered by normal huntingtin or by mutant caspase-1, two proteins shown to reduce inclusions and glutamine toxicity in other HD models. Thus, potential HD therapies in man might be directed at different levels: preventing the disease-initiating mechanism or slowing the subsequent progression of pathogenesis.
authors.affiliation: Molecular Neurogenetics Unit and Molecular Neuropathology, Massachusetts General Hospital, Charlestown, MA 02129, USA.
authors.forename: Vanessa C
authors.initials: VC
authors.lastname: Wheeler
authors.forename: Claire-Anne
authors.initials: CA
authors.lastname: Gutekunst
authors.forename: Vladimir
authors.initials: V
authors.lastname: Vrbanac
authors.forename: Lori-Anne
authors.initials: LA
authors.lastname: Lebel
authors.forename: Gabriele
authors.initials: G
authors.lastname: Schilling
authors.forename: Steven
authors.initials: S
authors.lastname: Hersch
authors.forename: Robert M
authors.initials: RM
authors.lastname: Friedlander
authors.forename: James F
authors.initials: JF
authors.lastname: Gusella
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Vonsattel
authors.forename: David R
authors.initials: DR
authors.lastname: Borchelt
authors.forename: Marcy E
authors.initials: ME
authors.lastname: MacDonald
mesh_terms: D000818:Animals; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism*; D005684:Gait / Q000502:physiology; D005799:Genes, Dominant; D005973:Glutamine / Q000235:genetics / Q000378:metabolism; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics*; D007155:Immunologic Factors; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016254:Mutagenesis, Insertional; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D013997:Time Factors; D018911:Trinucleotide Repeats / Q000235:genetics*
chemical_list: C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D007155:Immunologic Factors; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D005973:Glutamine; D020170:Caspase 1