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The novel Parkinson's disease linked mutation G51D attenuates in vitro aggregation and membrane binding of -synuclein, and enhances its secretion and nuclear localization in cells
Open accessAbstract
A novel mutation in the α-Synuclein (α-Syn) gene "G51D" was recently identified in two familial cases exhibiting features of Parkinson's disease (PD) and multiple system atrophy (MSA). In this study, we explored the impact of this novel mutation on the aggregation, cellular and biophysical properties of α-Syn, in an attempt to unravel how this mutant contributes to PD/MSA. Our results show that the G51D mutation significantly attenuates α-Syn aggregation in vitro. Moreover, it disrupts local helix formation in the presence of SDS, decreases binding to lipid vesicles C-terminal to the site of mutation and severely inhibits helical folding in the presence of acidic vesicles. When expressed in yeast, α-Syn(G51D) behaves similarly to α-Syn(A30P), as both exhibit impaired membrane association, form few inclusions and are non-toxic. In contrast, enhanced secreted and nuclear levels of the G51D mutant were observed in mammalian cells, as well as in primary neurons, where α-Syn(G51D) was enriched in the nuclear compartment, was hyper-phosphorylated at S129 and exacerbated α-Syn-induced mitochondrial fragmentation. Finally, post-mortem human brain tissues of α-Syn(G51D) cases were examined, and revealed only partial colocalization with nuclear membrane markers, probably due to post-mortem tissue delay and fixation. These findings suggest that the PD-linked mutations may cause neurodegeneration via different mechanisms, some of which may be independent of α-Syn aggregation.
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Cites
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Cited by
α-synuclein toxicity in neurodegeneration: mechanism and therapeutic strategies
Wong, Y. C., & Krainc, D. (2017) · Nature Medicine · doi:10.1038/nm.4269 · Cited by 897
Mahul-Mellier, A.-L., Burtscher, J., Maharjan, N., Weerens, L., Croisier, M., Kuttler, F., Leleu, M., Knott, G. W., & Lashuel, H. A. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1913904117 · Cited by 710
Self-citationLipid droplet biogenesis and functions in health and disease
Zadoorian, A., Du, X., & Yang, H. (2023) · Nature Reviews Endocrinology · doi:10.1038/s41574-023-00845-0 · Cited by 617
Cell Biology and Pathophysiology of α-Synuclein
Burré, J., Sharma, M., & Südhof, T. C. (2018) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a024091 · Cited by 579
α-Synuclein misfolding and aggregation: Implications in Parkinson’s disease pathogenesis
Mehra, S., Sahay, S., & Maji, S. K. (2019) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2019.03.001 · Cited by 499
Metadata
- Authors
- Fares, M.-B., Ait-Bouziad, N., Dikiy, I., Mbefo, M. K., Jovi i, A., Kiely, A., Holton, J. L., Lee, S.-J., Gitler, A. D., Eliezer, D., & Lashuel, H. A.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2014-04-11
- Volume
- 23
- Issue
- 17
- Pages
- 4491-4509
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2158490078
- Cited by
- 241
- References
- 8
- FWCI
- 10.48
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Fares, M.-B., Ait-Bouziad, N., Dikiy, I., Mbefo, M. K., Jovi i, A., Kiely, A., Holton, J. L., Lee, S.-J., Gitler, A. D., Eliezer, D., & Lashuel, H. A. (2014). The novel Parkinson's disease linked mutation G51D attenuates in vitro aggregation and membrane binding of -synuclein, and enhances its secretion and nuclear localization in cells. Human Molecular Genetics. https://doi.org/10.1093/hmg/ddu165
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