title: Polyglutamine-expanded ataxin-7 promotes non-cell-autonomous purkinje cell degeneration and displays proteolytic cleavage in ataxic transgenic mice.
abstract: Spinocerebellar ataxia (SCA) type 7 is an inherited neurodegenerative disorder caused by expansion of a polyglutamine tract within the ataxin-7 protein. To determine the molecular basis of polyglutamine neurotoxicity in this and other related disorders, we produced SCA7 transgenic mice that express ataxin-7 with 24 or 92 glutamines in all neurons of the CNS, except for Purkinje cells. Transgenic mice expressing ataxin-7 with 92 glutamines (92Q) developed a dramatic neurological phenotype presenting as a gait ataxia and culminating in premature death. Despite the absence of expression of polyglutamine-expanded ataxin-7 in Purkinje cells, we documented severe Purkinje cell degeneration in 92Q SCA7 transgenic mice. We also detected an N-terminal truncation fragment of ataxin-7 in transgenic mice and in SCA7 patient material with both anti-ataxin-7 and anti-polyglutamine specific antibodies. The appearance of truncated ataxin-7 in nuclear aggregates correlates with the onset of a disease phenotype in the SCA7 mice, suggesting that nuclear localization and proteolytic cleavage may be important features of SCA7 pathogenesis. The non-cell-autonomous nature of the Purkinje cell degeneration in our SCA7 mouse model indicates that polyglutamine-induced dysfunction in adjacent or connecting cell types contributes to the neurodegeneration.
authors.affiliation: Department of Neurology, University of Washington Medical Center, Seattle, Washington 98195-7110, USA.
authors.forename: Gwenn A
authors.initials: GA
authors.lastname: Garden
authors.forename: Randell T
authors.initials: RT
authors.lastname: Libby
authors.forename: Ying-Hui
authors.initials: YH
authors.lastname: Fu
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Kinoshita
authors.forename: Jing
authors.initials: J
authors.lastname: Huang
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Possin
authors.forename: Annette C
authors.initials: AC
authors.lastname: Smith
authors.forename: Refugio A
authors.initials: RA
authors.lastname: Martinez
authors.forename: Gabriel C
authors.initials: GC
authors.lastname: Fine
authors.forename: Sara K
authors.initials: SK
authors.lastname: Grote
authors.forename: Carol B
authors.initials: CB
authors.lastname: Ware
authors.forename: David D
authors.initials: DD
authors.lastname: Einum
authors.forename: Richard S
authors.initials: RS
authors.lastname: Morrison
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Ptacek
authors.forename: Bryce L
authors.initials: BL
authors.lastname: Sopher
authors.forename: Albert R
authors.initials: AR
authors.lastname: La Spada
mesh_terms: D000818:Animals; D000067719:Ataxin-7; D002467:Cell Nucleus / Q000473:pathology; D020234:Gait Ataxia / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D002479:Inclusion Bodies / Q000473:pathology; D007700:Kinetics; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D010455:Peptides / Q000235:genetics*; D011689:Purkinje Cells / Q000473:pathology*; D013132:Spinocerebellar Degenerations / Q000209:etiology* / Q000378:metabolism / Q000473:pathology
chemical_list: D000067719:Ataxin-7; C000593831:Atxn7 protein, mouse; D009419:Nerve Tissue Proteins; D010455:Peptides; C097188:polyglutamine