ArticleHuman molecular genetics2010
Beta-III spectrin mutation L253P associated with spinocerebellar ataxia type 5 interferes with binding to Arp1 and protein trafficking from the Golgi.
Article in Human molecular genetics, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 53 citations in OpenAlex.
- SPTBN2 suppresses ferroptosis in NSCLC cells by facilitating SLC7A11 membrane trafficking and localization.Redox biology · 2024Article
- Increased Actin Binding Is a Shared Molecular Consequence of Numerous SCA5 Mutations in β-III-Spectrin.Cells · 2023Article
- Increased actin binding is a shared molecular consequence of numerous spinocerebellar ataxia mutations in β-III-spectrin.bioRxiv : the preprint server for biology · 2023Article
- Spectrins: molecular organizers and targets of neurological disorders.Nature reviews. Neuroscience · 2023Review
- Clinical and functional characterization of a novel STUB1 frameshift mutation in autosomal dominant spinocerebellar ataxia type 48 (SCA48).Journal of biomedical science · 2021Article
- Heterozygous variants in SPTBN1 cause intellectual disability and autism.American journal of medical genetics. Part A · 2021Article
- Age-dependent ataxia and neurodegeneration caused by an αII spectrin mutation with impaired regulation of its calpain sensitivity.Scientific reports · 2021Article
- Expanding the β-III Spectrin-Associated Phenotypes toward Non-Progressive Congenital Ataxias with Neurodegeneration.International journal of molecular sciences · 2021Article
- CHIP as a therapeutic target for neurological diseases.Cell death & disease · 2020Review
- Excitatory Amino Acid Transporters in Physiology and Disorders of the Central Nervous System.International journal of molecular sciences · 2019Review
- A Novel Homozygous Mutation in SPTBN2 Leads to Spinocerebellar Ataxia in a Consanguineous Family: Report of a New Infantile-Onset Case and Brief Review of the Literature.Cerebellum (London, England) · 2018Review
- β-III-spectrin spinocerebellar ataxia type 5 mutation reveals a dominant cytoskeletal mechanism that underlies dendritic arborization.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Diverse mitotic functions of the cytoskeletal cross-linking protein Shortstop suggest a role in Dynein/Dynactin activity.Molecular biology of the cell · 2017Article
- Posterior cerebellar Purkinje cells in an SCA5/SPARCA1 mouse model are especially vulnerable to the synergistic effect of loss of β-III spectrin and GLAST.Human molecular genetics · 2016Article
- Cerebellar ataxias: β-III spectrin's interactions suggest common pathogenic pathways.The Journal of physiology · 2016Review
- A human β-III-spectrin spinocerebellar ataxia type 5 mutation causes high-affinity F-actin binding.Scientific reports · 2016Article
- De novo point mutations in patients diagnosed with ataxic cerebral palsy.Brain : a journal of neurology · 2015Article
- Connecting the cytoskeleton to the endoplasmic reticulum and Golgi.Current biology : CB · 2014Review
- β-III spectrin underpins ankyrin R function in Purkinje cell dendritic trees: protein complex critical for sodium channel activity is impaired by SCA5-associated mutations.Human molecular genetics · 2014Article
- Genetic studies of spectrin in the larval fat body of Drosophila melanogaster: evidence for a novel lipid uptake apparatus.Genetics · 2013Article
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
Abstract
Spinocerebellar ataxia type 5 (SCA5) is an autosomal dominant neurodegenerative disorder caused by mutations in beta-III spectrin. A mouse lacking full-length beta-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) beta-III spectrin function. Cell culture studies using beta-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, L253P beta-III spectrin prevents correct localization of WT beta-III spectrin and prevents EAAT4, a protein known to interact with beta-III spectrin, from reaching the plasma membrane. Interaction of beta-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 degrees C) rescues L253P beta-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 both beta-III spectrin and EAAT4 from the Golgi is disrupted through failure of the L253P mutation to interact with Arp1.
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