title: The ataxia (axJ) mutation causes abnormal GABAA receptor turnover in mice.
abstract: Ataxia represents a pathological coordination failure that often involves functional disturbances in cerebellar circuits. Purkinje cells (PCs) characterize the only output neurons of the cerebellar cortex and critically participate in regulating motor coordination. Although different genetic mutations are known that cause ataxia, little is known about the underlying cellular mechanisms. Here we show that a mutated ax(J) gene locus, encoding the ubiquitin-specific protease 14 (Usp14), negatively influences synaptic receptor turnover. Ax(J) mouse mutants, characterized by cerebellar ataxia, display both increased GABA(A) receptor (GABA(A)R) levels at PC surface membranes accompanied by enlarged IPSCs. Accordingly, we identify physical interaction of Usp14 and the GABA(A)R alpha1 subunit. Although other currently unknown changes might be involved, our data show that ubiquitin-dependent GABA(A)R turnover at cerebellar synapses contributes to ax(J)-mediated behavioural impairment.
authors.affiliation: Zentrum für Molekulare Neurobiologie Hamburg, Universität Hamburg, Hamburg, Germany.
authors.forename: Corinna
authors.initials: C
authors.lastname: Lappe-Siefke
authors.forename: Sven
authors.initials: S
authors.lastname: Loebrich
authors.forename: Wulf
authors.initials: W
authors.lastname: Hevers
authors.forename: Oliver B
authors.initials: OB
authors.lastname: Waidmann
authors.forename: Michaela
authors.initials: M
authors.lastname: Schweizer
authors.forename: Susanne
authors.initials: S
authors.lastname: Fehr
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Fritschy
authors.forename: Ivan
authors.initials: I
authors.lastname: Dikic
authors.forename: Jens
authors.initials: J
authors.lastname: Eilers
authors.forename: Scott M
authors.initials: SM
authors.lastname: Wilson
authors.forename: Matthias
authors.initials: M
authors.lastname: Kneussel
mesh_terms: D000818:Animals; D001259:Ataxia / Q000235:genetics* / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D011485:Protein Binding; D011689:Purkinje Cells / Q000378:metabolism; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000235:genetics* / Q000378:metabolism
chemical_list: D011963:Receptors, GABA-A; C469268:Usp14 protein, mouse; D043222:Ubiquitin Thiolesterase