Polyglutamine-expanded ataxin-7 promotes non-cell-autonomous purkinje cell degeneration and displays proteolytic cleavage in ataxic transgenic mice.
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.
Garden
Gwenn A
GA
Department of Neurology, University of Washington Medical Center, Seattle, Washington 98195-7110, USA.
Libby
Randell T
RT
Fu
Ying-Hui
YH
Kinoshita
Yoshito
Y
Huang
Jing
J
Possin
Daniel E
DE
Smith
Annette C
AC
Martinez
Refugio A
RA
Fine
Gabriel C
GC
Grote
Sara K
SK
Ware
Carol B
CB
Einum
David D
DD
Morrison
Richard S
RS
Ptacek
Louis J
LJ
Sopher
Bryce L
BL
La Spada
Albert R
AR
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
D000067719:Ataxin-7; C000593831:Atxn7 protein, mouse; D009419:Nerve Tissue Proteins; D010455:Peptides; C097188:polyglutamine