Myoclonus dystonia (MD) is a neurogenic movement disorder that can be caused by mutations in the SGCE gene encoding ε-sarcoglycan. ε-sarcoglycan belongs to the sarcoglycan family of cell surface-localised, single-pass transmembrane proteins originally identified in muscle where they form a heterotetrameric subcomplex of the dystrophin-associated glycoprotein complex (DGC). Mutations in the SGCA, SGCB, SGCG and SGCD genes encoding α-, β-, γ- and δ-sarcoglycan cause limb-girdle muscular dystrophy (LGMD). There is no phenotypic overlap between MD and LGMD. LGMD-associated sarcoglycan mutations impair trafficking of the entire sarcoglycan complex to the cell surface and destabilise the DGC in muscle, while MD-associated mutations typically result in loss of ε-sarcoglycan from the cell surface. This suggests cell surface ε-sarcoglycan but not other sarcoglycans is required for normal brain function. To gain insight into ε-sarcoglycan’s function(s) in the brain, immunoaffinity purification was used to identify ε-sarcoglycan-interacting proteins. Ubiquitous and brain-specific ε-sarcoglycan isoforms co-purified with three other sarcoglycans including ζ-sarcoglycan (encoded by SGCZ) from the brain. Incorporation of an LGMD-associated β-sarcoglycan mutant into the brain sarcoglycan complex impaired the formation of the βδ-sarcoglycan core but failed to abrogate the association and trafficking of ε- and ζ-sarcoglycan in heterologous cells. Both ε-sarcoglycan isoforms also co-purified with β-dystroglycan, indicating inclusion in DGC-like complexes. Additionally, the brain-specific ε-sarcoglycan isoform co-purified with the perineuronal net component tenascin-R, potentially suggesting a unique function for this isoform in modulating synapses. In common with SGCE, transcripts from the genes encoding α-, β-, δ-, γ- and ζ-sarcoglycans were found to undergo extensive alternative splicing, in some cases producing novel isoforms that affected assembly and trafficking of the sarcoglycan complex. In summary, data presented herein show that alternatively spliced sarcoglycan isoforms are part of the DGC in brain. These data contribute to our understanding of MD pathophysiology and the role of the sarcoglycan protein family.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:704913 |
| Date | January 2016 |
| Creators | Carlisle, Francesca |
| Publisher | Cardiff University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://orca.cf.ac.uk/97802/ |
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