title: Potassium channel dysfunction and depolarized resting membrane potential in a cell model of SCA3.
abstract: Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant inherited neurodegenerative disease caused by the expansion of a polyglutamine repeat within the disease protein, ataxin-3. There is growing evidence that neuronal electrophysiological properties are altered in a variety of polyglutamine diseases such as Huntington's disease and SCA1 and that these alterations may contribute to disturbances of neuronal function prior to neurodegeneration. To elucidate possible electrophysiological changes in SCA3, we generated a stable PC12 cell model with inducible expression of normal and mutant human full-length ataxin-3 and analyzed the electrophysiological properties after induction of the recombinant ataxin-3 expression. Neuronally differentiated PC12 cells expressing the expanded form of ataxin-3 showed significantly decreased viabilities and developed ultrastructural changes resembling human SCA3. Prior to neuronal cell death, we found a significant reduction of the resting membrane potential and a hyperpolarizing shift of the activation curve of the delayed rectifier potassium current. These findings indicate that electrophysiological properties are altered in mutant ataxin-3 expressing neuronal cells and may contribute to neuronal dysfunction in SCA3.
authors.affiliation: Department of Neurology, University of Bonn Medical Center, Sigmund Freud-Strasse 25, D-53105 Bonn, Germany. monika.jeub@ukb.uni-bonn.de
authors.forename: Monika
authors.initials: M
authors.lastname: Jeub
authors.forename: Martin
authors.initials: M
authors.lastname: Herbst
authors.forename: Alexander
authors.initials: A
authors.lastname: Spauschus
authors.forename: Henrik
authors.initials: H
authors.lastname: Fleischer
authors.forename: Thomas
authors.initials: T
authors.lastname: Klockgether
authors.forename: Ullrich
authors.initials: U
authors.lastname: Wuellner
authors.forename: Bernd O
authors.initials: BO
authors.lastname: Evert
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000067699:Ataxin-3; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D051668:Delayed Rectifier Potassium Channels / Q000502:physiology*; D004318:Doxycycline / Q000494:pharmacology; D006801:Humans; D017827:Machado-Joseph Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008854:Microscopy, Electron; D009154:Mutation / Q000235:genetics; D020932:Nerve Growth Factor / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000502:physiology / Q000648:ultrastructure; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D016716:PC12 Cells; D051381:Rats; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D013779:Tetrodotoxin / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection
chemical_list: D051668:Delayed Rectifier Potassium Channels; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D013779:Tetrodotoxin; D020932:Nerve Growth Factor; C092341:ATXN3 protein, human; D000067699:Ataxin-3; C511593:Atxn3 protein, rat; D004318:Doxycycline