The novel Parkinson's disease linked mutation G51D attenuates in vitro aggregation and membrane binding of α-synuclein, and enhances its secretion and nuclear localization in cells

Mohamed Bilal Fares, Nadine Ait-Bouziad, Igor Dikiy, Martial K. Mbefo, Ana Jovičić, Aoife Kiely, Janice L. Holton, Seung Jae Lee, Aaron D. Gitler, David Eliezer, Hilal A. Lashuel

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Abstract

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-SynG51D behaves similarly to α-SynA30P, 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-SynG51D 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-SynG51D 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.

Original languageEnglish
Article numberddu165
Pages (from-to)4491-4509
Number of pages19
JournalHuman Molecular Genetics
Volume23
Issue number17
DOIs
Publication statusPublished - 1 Jan 2014
Externally publishedYes

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ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Fares, M. B., Ait-Bouziad, N., Dikiy, I., Mbefo, M. K., Jovičić, 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 α-synuclein, and enhances its secretion and nuclear localization in cells. Human Molecular Genetics, 23(17), 4491-4509. [ddu165]. https://doi.org/10.1093/hmg/ddu165