Mutant ?-III spectrin causes mGluR1? mislocalization and functional deficits in a mouse model of spinocerebellar ataxia type 5.

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 ?-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 ?-III spectrin causes progressive motor deficits and cerebellar degeneration. We show that endogenous ?-III spectrin interacts with the metabotropic glutamate receptor 1? (mGluR1?) and that mice expressing mutant ?-III spectrin have cerebellar dysfunction with altered mGluR1? localization at Purkinje cell dendritic spines, decreased mGluR1-mediated responses, and deficient mGluR1-mediated long-term potentiation. These results indicate that mutant ?-III spectrin causes mislocalization and dysfunction of mGluR1? at dendritic spines and connects SCA5 with other disorders involving glutamatergic dysfunction and synaptic plasticity abnormalities.

SUBMITTER: Armbrust KR 

PROVIDER: S-EPMC4107406 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature