title: Spinocerebellar ataxia type 6 protein aggregates cause deficits in motor learning and cerebellar plasticity.
abstract: Spinocerebellar ataxia type 6 (SCA6) is linked to poly-glutamine (polyQ) within the C terminus (CT) of the pore-forming subunits of P/Q-type Ca(2+) channels (Cav2.1) and is characterized by CT protein aggregates found in cerebellar Purkinje cells (PCs). One hypothesis regarding SCA6 disease is that a CT fragment of the Cav2.1 channel, which is detected specifically in cytosolic and nuclear fractions in SCA6 patients, is associated with the SCA6 pathogenesis. To test this hypothesis, we expressed P/Q-type channel protein fragments from two different human CT splice variants, as predicted from SCA6 patients, in PCs of mice using viral and transgenic approaches. These splice variants represent a short (CT-short without polyQs) and a long (CT-long with 27 polyQs) CT fragment. Our results show that the different splice variants of the CTs differentially distribute within PCs, i.e., the short CTs reveal predominantly nuclear inclusions, whereas the long CTs prominently reveal both nuclear and cytoplasmic aggregates. Postnatal expression of CTs in PCs in mice reveals that only CT-long causes SCA6-like symptoms, i.e., deficits in eyeblink conditioning (EBC), ataxia, and PC degeneration. The physiological phenotypes associated specifically with the long CT fragment can be explained by an impairment of LTD and LTP at the parallel fiber-to-PC synapse and alteration in spontaneous PC activity. Thus, our results suggest that the polyQ carrying the CT fragment of the P/Q-type channel is sufficient to cause SCA6 pathogenesis in mice and identifies EBC as a new diagnostic strategy to evaluate Ca(2+) channel-mediated human diseases.
authors.affiliation: Department of Zoology and Neurobiology, Ruhr University Bochum, D-44780 Bochum, Germany, melanie.mark@rub.de.
authors.forename: Melanie D
authors.identifier: http://orcid.org/0000-0002-2788-6003
authors.initials: MD
authors.lastname: Mark
authors.affiliation: Department of Zoology and Neurobiology, Ruhr University Bochum, D-44780 Bochum, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Krause
authors.affiliation: Department of Neuroscience, Erasmus Medical Center, 3000 DR Rotterdam, The Netherlands.
authors.forename: Henk-Jan
authors.initials: HJ
authors.lastname: Boele
authors.affiliation: Department of Zoology and Neurobiology, Ruhr University Bochum, D-44780 Bochum, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Kruse
authors.affiliation: Department of Zoology and Neurobiology, Ruhr University Bochum, D-44780 Bochum, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Pollok
authors.affiliation: Department of Functional Neuroanatomy, Institute of Anatomy and Cell Biology, Heidelberg University, D-69120 Heidelberg, Germany.
authors.forename: Thomas
authors.identifier: http://orcid.org/0000-0003-1896-9031
authors.initials: T
authors.lastname: Kuner
authors.affiliation: Vision Institute, F-75012 Paris, France, and.
authors.forename: Deniz
authors.initials: D
authors.lastname: Dalkara
authors.affiliation: Department of Neuroscience, Erasmus Medical Center, 3000 DR Rotterdam, The Netherlands.
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: Koekkoek
authors.affiliation: Department of Neuroscience, Erasmus Medical Center, 3000 DR Rotterdam, The Netherlands, Netherlands Institute for Neuroscience, Royal Dutch Academy of Arts and Sciences, 1105 BA Amsterdam, The Netherlands.
authors.forename: Chris I
authors.initials: CI
authors.lastname: De Zeeuw
authors.affiliation: Department of Zoology and Neurobiology, Ruhr University Bochum, D-44780 Bochum, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Herlitze
mesh_terms: D000199:Actins / Q000378:metabolism; D000200:Action Potentials / Q000235:genetics; D000367:Age Factors; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics; D020864:Calcium Channels, N-Type / Q000235:genetics; D002525:Cerebellar Cortex / Q000473:pathology; D002531:Cerebellum / Q000473:pathology*; D004195:Disease Models, Animal; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D066298:In Vitro Techniques; D007859:Learning Disabilities / Q000235:genetics*; D008164:Luminescent Proteins / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics; D009473:Neuronal Plasticity / Q000235:genetics*; D009474:Neurons / Q000473:pathology / Q000502:physiology*; D010455:Peptides / Q000235:genetics; D066329:Protein Aggregates / Q000235:genetics*; D011597:Psychomotor Performance / Q000502:physiology; D020754:Spinocerebellar Ataxias / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D000199:Actins; D001426:Bacterial Proteins; D020864:Calcium Channels, N-Type; D008164:Luminescent Proteins; D010455:Peptides; D066329:Protein Aggregates; C054562:yellow fluorescent protein, Bacteria; C097188:polyglutamine
keywords: P/Q type calcium channel; poly-glutamine disease; spinocerebellar ataxia type 6