Reference : Differential regulation of wild-type and mutant alpha-synuclein binding to synaptic m...
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
Differential regulation of wild-type and mutant alpha-synuclein binding to synaptic membranes by cytosolic factors.
Wislet-Gendebien, Sabine mailto [Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biochimie et physiologie générales, et biochimie humaine >]
Visanji, Naomi P [> > > >]
Whitehead, Shawn N [> > > >]
Marsilio, Diana [> > > >]
Hou, Weimin [Université de Liège - ULiège > Département de chimie (sciences) > Nano-chimie et systèmes moléculaires >]
Figeys, Daniel [> > > >]
Fraser, Paul E [> > > >]
Bennett, Steffany A L [> > > >]
Tandon, Anurag [> > > >]
BMC Neuroscience
BioMed Central
Yes (verified by ORBi)
[en] Adenosine Triphosphate/analysis/metabolism ; Animals ; Blotting, Western ; Brain Chemistry ; Calcium/analysis/metabolism ; Cytosol/chemistry/metabolism ; Genotype ; Humans ; Lipids/analysis ; Membrane Proteins/chemistry/genetics/metabolism ; Mice ; Mice, Knockout ; Mutation ; Mutation, Missense ; Parkinson Disease/genetics/metabolism ; Platelet Activating Factor/analogs & derivatives/analysis/metabolism ; Protein Binding ; Synaptic Membranes/metabolism ; Synaptosomes/metabolism ; alpha-Synuclein/analysis/genetics/metabolism
[en] BACKGROUND: Alpha-Synuclein (alpha-syn), a 140 amino acid protein associated with presynaptic membranes in brain, is a major constituent of Lewy bodies in Parkinson's disease (PD). Three missense mutations (A30P, A53T and E46K) in the alpha-syn gene are associated with rare autosomal dominant forms of familial PD. However, the regulation of alpha-syn's cellular localization in neurons and the effects of the PD-linked mutations are poorly understood. RESULTS: In the present study, we analysed the ability of cytosolic factors to regulate alpha-syn binding to synaptic membranes. We show that co-incubation with brain cytosol significantly increases the membrane binding of normal and PD-linked mutant alpha-syn. To characterize cytosolic factor(s) that modulate alpha-syn binding properties, we investigated the ability of proteins, lipids, ATP and calcium to modulate alpha-syn membrane interactions. We report that lipids and ATP are two of the principal cytosolic components that modulate Wt and A53T alpha-syn binding to the synaptic membrane. We further show that 1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphocholine (C16:0 PAF) is one of the principal lipids found in complex with cytosolic proteins and is required to enhance alpha-syn interaction with synaptic membrane. In addition, the impaired membrane binding observed for A30P alpha-syn was significantly mitigated by the presence of protease-sensitive factors in brain cytosol. CONCLUSION: These findings suggest that endogenous brain cytosolic factors regulate Wt and mutant alpha-syn membrane binding, and could represent potential targets to influence alpha-syn solubility in brain.
Centre of Research in neurodegenerative disease
Canadian Institutes of Health Research (CIHR) ; Parkinson Society of Canada ; Leon Frederick Foundation ; Michael J Fox Foundation ; Alzheimer Society of Ontario ; Ontario Mental Health Foundation (OMHF)

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