Rovere, M;
Powers, AE;
Jiang, H;
Pitino, JC;
Fonseca-Ornelas, L;
Patel, DS;
Achille, A;
... Bartels, T; + view all
(2019)
E46K-like α-synuclein mutants increase lipid interactions and disrupt membrane selectivity.
Journal of Biological Chemistry
10.1074/jbc.RA118.006551.
(In press).
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J. Biol. Chem.-2019-Rovere-jbc.RA118.006551.pdf - Accepted Version Download (8MB) | Preview |
Abstract
Parkinson's disease (PD) is one of the most common neurodegenerative disorders and both genetic and histopathological evidence have implicated the ubiquitous presynaptic protein α-synuclein (αSyn) in its pathogenesis. Recent work has investigated how disrupting αSyn's interaction with membranes triggers trafficking defects, cellular stress, and apoptosis. Special interest has been devoted to a series of mutants exacerbating the effects of the E46K mutation (associated with autosomal dominant PD) through homologous E-to-K substitutions in αSyn's N-terminal region (i.e. E35K, E61K). Such E46K-like mutants have been shown to cause dopaminergic neuron loss and severe, yet L-DOPA-responsive, motor defects in mouse overexpression models, presenting enormous translational potential for PD and other "synucleinopathies". In this work, using a variety of biophysical techniques, we characterize the molecular pathology of E46K-like αSyn mutants by studying their structure and membrane-binding and remodeling abilities. We find that, although a slight increase in the mutants' avidity for synaptic vesicle-like membranes can be detected, most of their deleterious effects are connected to their complete disruption of αSyn's curvature selectivity. Indiscriminate binding can shift αSyn's subcellular localization away from its physiological interactants at the synaptic bouton toward trafficking vesicles and organelles, as observed in E46K-like cellular and murine models, as well as in human pathology. In conclusion, our findings suggest that a loss of curvature selectivity, rather than increased membrane affinity, could be the critical dyshomeostasis in synucleinopathies.
| Type: | Article |
|---|---|
| Title: | E46K-like α-synuclein mutants increase lipid interactions and disrupt membrane selectivity |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1074/jbc.RA118.006551 |
| Publisher version: | https://doi.org/10.1074/jbc.RA118.006551 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | 11/3 Helix, Large Unilamellar Vesicle, Parkinson disease, Small Unilamellar Vesicle, alpha-synuclein (a-synuclein), circular dichroism (CD), intrinsically disordered protein, isothermal titration calorimetry (ITC), neurodegeneration, protein-lipid interaction |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > UK Dementia Research Institute |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10075108 |
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