[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.
Research center :
Centre of Research in neurodegenerative disease
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Wislet-Gendebien, Sabine ; 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
Language :
English
Title :
Differential regulation of wild-type and mutant alpha-synuclein binding to synaptic membranes by cytosolic factors.
Publication date :
September 2008
Journal title :
BMC Neuroscience
eISSN :
1471-2202
Publisher :
BioMed Central, United Kingdom
Volume :
9
Pages :
92
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
CIHR - Canadian Institutes of Health Research [CA] PSC - Parkinson Society Canada [CA] Fondation Léon Fredericq [BE] MJFF - Michael J. Fox Foundation for Parkinson's Research [US-NY] [US-NY] ASC - Alzheimer Society of Canada [CA] OMHF - Ontario Mental Health Foundation [CA]
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