Mutant β-III Spectrin Causes mGluR1α Mislocalization and Functional Deficits in a Mouse Model of Spinocerebellar Ataxia Type 5

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