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: Parminder J S Vig, Jinrong Wei, Qingmei Shao, Maripar E Lopez, Rebecca Halperin, Jill Gerber
• Journal: Cerebellum (London, England) (Cerebellum) Vol. 11 Issue 3 Pg. 718-32 (Sep 2012) ISSN: 1473-4230 [Electronic] United States
• PMID: 22076800 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Ataxin-1
• Ataxins
• Atxn1 protein, mouse
• Calb1 protein, mouse
• Calbindin 1
• Calbindins
• Nerve Tissue Proteins
• Nuclear Proteins
• Parvalbumins
• S100 Calcium Binding Protein G

Topics

• Animals
• Ataxin-1
• Ataxins
• Behavior, Animal (physiology)
• Blotting, Western
• Calbindin 1
• Calbindins
• Cell Membrane (metabolism)
• Cell Nucleus (metabolism)
• Cytosol (metabolism)
• DNA Footprinting
• Female
• Immunohistochemistry
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Microarray Analysis
• Mutation (physiology)
• Nerve Tissue Proteins (genetics, metabolism)
• Nuclear Proteins (genetics, metabolism)
• Parvalbumins (metabolism)
• Phenotype
• Polymerase Chain Reaction
• Postural Balance (physiology)
• Psychomotor Performance (physiology)
• S100 Calcium Binding Protein G (biosynthesis, genetics)
• Spinocerebellar Ataxias (genetics, physiopathology)