Expanded polyglutamines induce neurodegeneration and trans-neuronal alterations in cerebellum and retina of SCA7 transgenic mice.
Among the eight progressive neurodegenerative diseases caused by polyglutamine expansions, spinocerebellar ataxia type 7 (SCA7) is the only one to display degeneration in both brain and retina. We show here that mice overexpressing full-length mutant ataxin-7[Q90] either in Purkinje cells or in rod photoreceptors have deficiencies in motor coordination and vision, respectively. In both models, although with different time courses, an N-terminal fragment of mutant ataxin-7 accumulates into ubiquitinated nuclear inclusions that recruit a distinct set of chaperone/proteasome subunits. A severe degeneration is caused by overexpression of ataxin-7[Q90] in rods, whereas a similar overexpression of normal ataxin-7[Q10] has no obvious effect. The degenerative process is not limited to photoreceptors, showing secondary alterations of post-synaptic neurons. These findings suggest that proteolytic cleavage of mutant ataxin-7 and trans-neuronal responses are implicated in the pathogenesis of SCA7.
Yvert
G
G
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, BP 163, 67404 Illkirch cedex, CU de Strasbourg, France.
Lindenberg
K S
KS
Picaud
S
S
Landwehrmeyer
G B
GB
Sahel
J A
JA
Mandel
J L
JL
D000818:Animals; D000067719:Ataxin-7; D002467:Cell Nucleus / Q000378:metabolism; D002531:Cerebellum / Q000648:ultrastructure; D004596:Electroretinography; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000378:metabolism; D009410:Nerve Degeneration / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D010455:Peptides / Q000235:genetics*; D010641:Phenotype; D011499:Protein Processing, Post-Translational; D011689:Purkinje Cells / Q000378:metabolism / Q000648:ultrastructure; D012160:Retina / Q000503:physiopathology; D012162:Retinal Degeneration / Q000235:genetics*; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism / Q000648:ultrastructure; D020754:Spinocerebellar Ataxias / Q000235:genetics*; D018911:Trinucleotide Repeats; D014452:Ubiquitins / Q000378:metabolism
C000593829:ATXN7 protein, human; D000067719:Ataxin-7; C000593831:Atxn7 protein, mouse; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins; D010455:Peptides; D014452:Ubiquitins; C097188:polyglutamine