Mutant β-III spectrin causes mGluR1α mislocalization and functional deficits in a mouse model of spinocerebellar ataxia type 5

Karen R. Armbrust, Xinming Wang, Tyisha J. Hathorn, Samuel W. Cramer, Gang Chen, Tao Zu, Takashi Kangas, Anastasia N. Zink, Gülin Öz, Timothy J. Ebner, Laura P W Ranum

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

Spinocerebellar ataxia type 5 (SCA5), a dominant neurodegenerative disease characterized by profound Purkinje cell loss, is caused by mutations in SPTBN2, a gene that encodes β-III spectrin. SCA5 is the first neurodegenerative disorder reported to be caused by mutations in a cytoskeletal spectrin gene. We have developed a mouse model to understand the mechanistic basis for this disease and show that expression of mutant but not wild-type β-III spectrin causes progressive motor deficits and cerebellar degeneration. We show that endogenous β-III spectrin interacts with the metabotropic glutamate receptor 1α (mGluR1α) and that mice expressing mutant β-III spectrin have cerebellar dysfunction with altered mGluR1α localization at Purkinje cell dendritic spines, decreased mGluR1-mediated responses, and deficient mGluR1-mediated long-term potentiation. These results indicate that mutant β-III spectrin causes mislocalization and dysfunction of mGluR1α at dendritic spines and connects SCA5 with other disorders involving glutamatergic dysfunction and synaptic plasticity abnormalities.

Original languageEnglish (US)
Pages (from-to)9891-9904
Number of pages14
JournalJournal of Neuroscience
Volume34
Issue number30
DOIs
StatePublished - 2014

Keywords

  • Long term potentiation
  • MGluR1a
  • Mouse model
  • Neurodegeneration
  • Purkinje cells
  • Spinocerebellar ataxia type 5

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