title: Deletion of Inpp5a causes ataxia and cerebellar degeneration in mice.
abstract: The progressive and permanent loss of cerebellar Purkinje cells (PC) is a hallmark of many inherited ataxias. Mutations in several genes involved in the regulation of Ca(2+) release from intracellular stores by the second messenger IP3 have been associated with PC dysfunction or death. While much is known about the defects in production and response to IP3, less is known about the defects in breakdown of the IP3 second messenger. A mutation in Inpp4a of the pathway is associated with a severe, early-onset PC degeneration in the mouse model weeble. The step preceding the removal of the 4-phosphate is the removal of the 5-phosphate by Inpp5a. Gene expression analysis was performed on an Inpp5a (Gt(OST50073)Lex) mouse generated by gene trap insertion using quantitative real-time PCR (qRT-PCR), immunohistochemistry, and Western blot. Phenotypic analyses were performed using rotarod, β-galactosidase staining, and phosphatase activity assay. Statistical significance was calculated. The deletion of Inpp5a causes an early-onset yet slowly progressive PC degeneration and ataxia. Homozygous mutants (90%) exhibit perinatal lethality; surviving homozygotes show locomotor instability at P16. A consistent pattern of PC loss in the cerebellum is initially detectable by weaning and widespread by P60. Phosphatase activity toward phosphoinositol substrates is reduced in the mutant relative to littermates. The ataxic phenotype and characteristics neurodegeneration of the Inpp5a (Gt(OST50073)Lex) mouse indicate a crucial role for Inpp5a in PC survival. The identification of the molecular basis of the selective PC survival will be important in defining a neuroprotective gene applicable to establishing a disease mechanism.
authors.affiliation: The Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA. ayang@unmc.edu.
authors.forename: Andy W
authors.initials: AW
authors.lastname: Yang
authors.affiliation: The Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA. xavior81@yahoo.com.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Sachs
authors.affiliation: The Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA. arne.nystuen@gmail.com.
authors.forename: Arne M
authors.initials: AM
authors.lastname: Nystuen
mesh_terms: D000818:Animals; D002524:Cerebellar Ataxia / Q000196:embryology / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D017353:Gene Deletion; D000072181:Inositol Polyphosphate 5-Phosphatases; D051379:Mice; D009043:Motor Activity / Q000235:genetics; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D011689:Purkinje Cells / Q000473:pathology; D045442:Rotarod Performance Test
chemical_list: D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606432:Inpp5a protein, mouse
keywords: Ataxia; Cerebellar degeneration; Inpp5a; Knockout mouse