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Substitution of Met-38 to Ile in gamma-synuclein found in two patients with amyotrophic lateral sclerosis induces aggregation into amyloid
Citation
Aubrey, Liam D. and Ulamec, Sabine M. and Ninkina, Natalia and Abramycheva, Natalia Y. and Limorenko, Galina and Vasili, Eftychia and Devine, Oliver M. and Wilkinson, Martin and Walko, Martin and Outeiro, Tiago F. and Chaprov, Kirill D. and Muwanga, Sarah and Amadio, Leonardo and Peters, Owen M. and Illarioshkin, Sergey N. and Ranson, Neil A. and Brockwell, David J. and Buchman, Vladimir L. and Radford, Sheena E. (2023) Substitution of Met-38 to Ile in gamma-synuclein found in two patients with amyotrophic lateral sclerosis induces aggregation into amyloid. University of Leeds. [Dataset] https://doi.org/10.5518/1315
Dataset description
α-, β-, and γ-Synuclein are intrinsically disordered proteins implicated in physiological processes in the nervous system of vertebrates. α-synuclein (αSyn) is the amyloidogenic protein associated with Parkinson’s disease and certain other neurodegenerative disorders. Intensive research has focused on the mechanisms that cause αSyn to form amyloid structures, identifying its NAC region as being necessary and sufficient for amyloid assembly. Recent work has shown that a 7-residue sequence (P1) is necessary for αSyn amyloid formation. Although γ-synuclein (γSyn) is 55% identical in sequence to αSyn and its pathological deposits are also observed in association with neurodegenerative conditions, γSyn is resilient to amyloid formation in vitro. Here, we report a rare single nucleotide polymorphism (SNP) in the SNCG gene encoding γSyn, found in two patients with amyotrophic lateral sclerosis (ALS). The SNP results in the substitution of Met38 with Ile in the P1 region of the protein. These individuals also had a second, common and nonpathological, SNP in SNCG resulting in the substitution of Glu110 with Val. In vitro studies demonstrate that the Ile38 variant accelerates amyloid fibril assembly. Contrastingly, Val110 retards fibril assembly and mitigates the effect of Ile38. Substitution of residue 38 with Leu had little effect, while Val retards, and Ala increases the rate of amyloid formation. Ile38 γSyn also results in the formation of γSyn-containing inclusions in cells. The results show how a single point substitution can enhance amyloid formation of γSyn and highlight the P1 region in driving amyloid formation in another synuclein family member.
| Keywords: | gamma-synuclein, ALS, aggregation, amyloid, oligomers | ||||||
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| Subjects: | C000 - Biological sciences > C700 - Molecular biology, biophysics & biochemistry > C770 - Biophysical science C000 - Biological sciences > C400 - Genetics > C450 - Genomics |
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| License: | Creative Commons Attribution 4.0 International (CC BY 4.0) | ||||||
| Date deposited: | 05 Jan 2024 10:47 | ||||||
| URI: | https://archive.researchdata.leeds.ac.uk/id/eprint/1214 | ||||||
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Documentation
readme [5kB]  |
readme [5kB] 
readme [5kB] Data
CD data [63kB] |
Differential pelleting [25kB] |
Liposome tht data [267kB] |
HPLC data [434kB] |
Beads and Shaking ThTs [696kB] |
percent of transfected neuroblastoma cells [83kB] |
Seeded_after_beads_and_shaking_ThT [203kB] |