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Spinocerebellar ataxia type 5 (SCA5) is an autosomal dominant neurodegenerative disorder caused by mutations inβ-III spectrin. A mouse lacking full-lengthβ-III spectrin has a phenotype closely mirroring symptoms of SCA5 patients. Here we report the analysis of heterozygous animals, which show no signs of ataxia or cerebellar degeneration up to 2 years of age. This argues against haploinsufficiency as a disease mechanism and points towards human mutations having a dominant-negative effect on wild-type (WT)β-III spectrin function. Cell culture studies usingβ-III spectrin with a mutation associated with SCA5 (L253P) reveal that mutant protein, instead of being found at the cell membrane, appears trapped in the cytoplasm associated with the Golgi apparatus. Furthermore, L253Pβ-III spectrin prevents correct localization of WTβ-III spectrin and prevents EAAT4, a protein known to interact withβ-III spectrin, from reaching the plasma membrane. Interaction ofβ-III spectrin with Arp1, a subunit of the dynactin–dynein complex, is also lost with the L253P substitution. Despite intracellular accumulation of proteins, this cellular stress does not induce the unfolded protein response, implying the importance of membrane protein loss in disease pathogenesis. Incubation at lower temperature (25°C) rescues L253Pβ-III spectrin interaction with Arp1 and normal protein trafficking to the membrane. These data provide evidence for a dominant-negative effect of an SCA5 mutation and show for the first time that trafficking of bothβ-III spectrin and EAAT4 from the Golgi is disrupted through failure of the L253P mutation to interact with Arp1.

β-III spectrin mutation L253P associated with spinocerebellar ataxia type 5 interferes with binding to Arp1 and protein trafficking from the Golgi