Recovery from polyglutamine-induced neurodegeneration in conditional SCA1 transgenic mice.
Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant, polyglutamine-induced neurodegenerative disorder that results in loss of motor coordination caused primarily by a disruption of cerebellar Purkinje cell function. In this study, we developed a conditional SCA1 mouse model to examine whether stopping expression of mutant ataxin-1 alters the disease phenotype. After cessation of SCA1[82Q] transgene expression, mutant ataxin-1, including that in nuclear inclusions, was cleared rapidly from Purkinje cells. At an early stage of disease, Purkinje cell pathology and motor dysfunction were completely reversible. After halting SCA1 expression at later stages of disease, only a partial recovery was seen. Interestingly, restoration of the ability to perform a complex motor task, the accelerating Rotarod, correlated with localization of mGluR1alpha to the Purkinje cell-parallel fiber synapse. These results show that the progression of SCA1 pathogenesis is dependent on the continuous expression of mutant ataxin-1. Of note, even at a late stage of disease, Purkinje cells retain at least some ability to repair the damage caused by mutant ataxin-1.
Institute of Human Genetics, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Tao
T
Zu
Lisa A
LA
Duvick
Michael D
MD
Kaytor
Michael S
MS
Berlinger
Huda Y
HY
Zoghbi
H Brent
HB
Clark
Harry T
HT
Orr
D000818:Animals; D000067696:Ataxin-1; D000067528:Ataxins; D042622:DNA Repeat Expansion; D004195:Disease Models, Animal; D018450:Disease Progression; D004318:Doxycycline / Q000494:pharmacology; D005786:Gene Expression Regulation; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000235:genetics*; D009687:Nuclear Proteins / Q000032:analysis / Q000235:genetics*; D010455:Peptides / Q000235:genetics; D011689:Purkinje Cells / Q000737:chemistry / Q000473:pathology*; D018094:Receptors, Metabotropic Glutamate / Q000032:analysis; D045442:Rotarod Performance Test; D020754:Spinocerebellar Ataxias / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D013569:Synapses / Q000737:chemistry
C000593749:ATXN1 protein, human; D000067696:Ataxin-1; D000067528:Ataxins; C000593750:Atxn1 protein, mouse; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; C097188:polyglutamine; D004318:Doxycycline