title: Suppression of calbindin-D28k expression exacerbates SCA1 phenotype in a disease mouse model.
abstract: Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurological disorder caused by the expansion of a polyglutamine tract in the mutant protein ataxin-1. The cerebellar Purkinje cells (PCs) are the major targets of mutant ataxin-1. The mechanism of PC death in SCA1 is not known; however, previous work indicates that downregulation of specific proteins involved in calcium homeostasis and signaling by mutant ataxin-1 is the probable cause of PC degeneration in SCA1. In this study, we explored if targeted deprivation of PC specific calcium-binding protein calbindin-D28k (CaB) exacerbates ataxin-1 mediated toxicity in SCA1 transgenic (Tg) mice. Using behavioral tests, we found that though both SCA1/+ and SCA1/+: CaB null (-/+) double mutants exhibited progressive impaired performance on the rotating rod, a simultaneous enhancement of exploratory activity, and absence of deficits in coordination, the double mutants were more severely impaired than SCA1/+ mice. With increasing age, SCA1/+ mice showed a progressive loss in the expression and localization of CaB and other PC specific calcium-binding and signaling proteins. In double mutants, these changes were more pronounced and had an earlier onset. Gene expression profiling of young mice exhibiting no behavior or biochemical deficits revealed a differential expression of many genes common to SCA1/+ and CaB-/+ lines, and unique to SCA1/+: CaB-/+ phenotype. Our study provides further evidence for a critical role of CaB in SCA1 pathogenesis, which may help identify new therapeutic targets to treat SCA1 or other cerebellar ataxias.
authors.affiliation: Department of Neurology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA. pvig@umc.edu
authors.forename: Parminder J S
authors.initials: PJ
authors.lastname: Vig
authors.forename: Jinrong
authors.initials: J
authors.lastname: Wei
authors.forename: Qingmei
authors.initials: Q
authors.lastname: Shao
authors.forename: Maripar E
authors.initials: ME
authors.lastname: Lopez
authors.forename: Rebecca
authors.initials: R
authors.lastname: Halperin
authors.forename: Jill
authors.initials: J
authors.lastname: Gerber
mesh_terms: D000818:Animals; D000067696:Ataxin-1; D000067528:Ataxins; D001522:Behavior, Animal / Q000502:physiology; D015153:Blotting, Western; D064092:Calbindin 1; D064026:Calbindins; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D018983:DNA Footprinting; D005260:Female; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046228:Microarray Analysis; D009154:Mutation / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010320:Parvalbumins / Q000378:metabolism; D010641:Phenotype; D016133:Polymerase Chain Reaction; D004856:Postural Balance / Q000502:physiology; D011597:Psychomotor Performance / Q000502:physiology; D064030:S100 Calcium Binding Protein G / Q000096:biosynthesis* / Q000235:genetics; D020754:Spinocerebellar Ataxias / Q000235:genetics* / Q000503:physiopathology*
chemical_list: D000067696:Ataxin-1; D000067528:Ataxins; C000593750:Atxn1 protein, mouse; C576499:Calb1 protein, mouse; D064092:Calbindin 1; D064026:Calbindins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010320:Parvalbumins; D064030:S100 Calcium Binding Protein G
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