title: Mutant β-III spectrin causes mGluR1α 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 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.
authors: Departments of Genetics, Cell Biology and Development.
authors: Karen R
authors: KR
authors: Armbrust
authors: Neuroscience, and.
authors: Xinming
authors: X
authors: Wang
authors: Center for NeuroGenetics, Department of Molecular Genetics and Microbiology, Genetics Institute, College of Medicine, University of Florida, Gainesville, Florida 32610.
authors: Tyisha J
authors: TJ
authors: Hathorn
authors: Neuroscience, and.
authors: Samuel W
authors: http://orcid.org/0000-0002-7103-4182
authors: SW
authors: Cramer
authors: Neuroscience, and.
authors: Gang
authors: G
authors: Chen
authors: Center for NeuroGenetics, Department of Molecular Genetics and Microbiology, Genetics Institute, College of Medicine, University of Florida, Gainesville, Florida 32610.
authors: Tao
authors: T
authors: Zu
authors: Departments of Genetics, Cell Biology and Development.
authors: Takashi
authors: T
authors: Kangas
authors: Departments of Genetics, Cell Biology and Development.
authors: Anastasia N
authors: AN
authors: Zink
authors: Center for Magnetic Resonance Research, University of Minnesota, Minneapolis, Minnesota 55455 and.
authors: Gülin
authors: G
authors: Öz
authors: Neuroscience, and.
authors: Timothy J
authors: TJ
authors: Ebner
authors: Departments of Genetics, Cell Biology and Development, Center for NeuroGenetics, Department of Molecular Genetics and Microbiology, Department of Neurology, and Genetics Institute, College of Medicine, University of Florida, Gainesville, Florida 32610 ranum@ufl.edu.
authors: Laura P W
authors: LP
authors: Ranum
mesh_terms: D000818:Animals; D002531:Cerebellum / Q000737:chemistry / Q000473:pathology; D049229:Dendritic Spines / Q000737:chemistry / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D018094:Receptors, Metabotropic Glutamate / Q000032:analysis* / Q000235:genetics* / Q000378:metabolism; D013049:Spectrin / Q000235:genetics*; D020754:Spinocerebellar Ataxias / Q000235:genetics* / Q000503:physiopathology
chemical_list: D018094:Receptors, Metabotropic Glutamate; C495133:SPTBN2 protein, human; C104077:metabotropic glutamate receptor type 1; D013049:Spectrin
keywords: Purkinje cells; long term potentiation; mGluR1α; mouse model; neurodegeneration; spinocerebellar ataxia type 5