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J Neurosci. 2015 Jun 10;35(23):8882-95. doi: 10.1523/JNEUROSCI.0891-15.2015.

Spinocerebellar ataxia type 6 protein aggregates cause deficits in motor learning and cerebellar plasticity.

Author information

  • 1Department of Zoology and Neurobiology, Ruhr University Bochum, D-44780 Bochum, Germany,
  • 2Department of Zoology and Neurobiology, Ruhr University Bochum, D-44780 Bochum, Germany.
  • 3Department of Neuroscience, Erasmus Medical Center, 3000 DR Rotterdam, The Netherlands.
  • 4Department of Functional Neuroanatomy, Institute of Anatomy and Cell Biology, Heidelberg University, D-69120 Heidelberg, Germany.
  • 5Vision Institute, F-75012 Paris, France, and.
  • 6Department 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.

Erratum in

  • J Neurosci. 2015 Sep 9;35(36):12606-7.


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.

Copyright © 2015 the authors 0270-6474/15/358882-14$15.00/0.


P/Q type calcium channel; poly-glutamine disease; spinocerebellar ataxia type 6

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