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RSS FeedsE46K-like {alpha}-synuclein mutants increase lipid interactions and disrupt membrane selectivity [Molecular Biophysics] (Journal of Biological Chemistry)

 
 

21 june 2019 16:02:46

 
E46K-like {alpha}-synuclein mutants increase lipid interactions and disrupt membrane selectivity [Molecular Biophysics] (Journal of Biological Chemistry)
 


Parkinson`s disease (PD) is one of the most common neurodegenerative disorders, and both genetic and histopathological evidence have implicated the ubiquitous presynaptic protein ?-synuclein (?Syn) in its pathogenesis. Recent work has investigated how disrupting ?Syn`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 Glu-to-Lys substitutions in ?Syn`s N-terminal region (i.e. E35K and E61K). Such E46K-like mutants have been shown to cause dopaminergic neuron loss and severe but 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 ?Syn 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 ?Syn`s curvature selectivity. Indiscriminate binding can shift ?Syn`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.


 
63 viewsCategory: Biochemistry
 
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