[en] Intracellular accumulation of insoluble alpha-synuclein in Lewy bodies is a key neuropathological trait of Parkinson disease (PD). Neither the normal function of alpha-synuclein nor the biochemical mechanisms that cause its deposition are understood, although both are likely influenced by the interaction of alpha-synuclein with vesicular membranes, either for a physiological role in vesicular trafficking or as a pathological seeding mechanism that exacerbates the propensity of alpha-synuclein to self-assemble into fibrils. In addition to the alpha-helical form that is peripherally-attached to vesicles, a substantial portion of alpha-synuclein is freely diffusible in the cytoplasm. The mechanisms controlling alpha-synuclein exchange between these compartments are unknown and the possibility that chronic dysregulation of membrane-bound and soluble alpha-synuclein pools may contribute to Lewy body pathology led us to search for cellular factors that can regulate alpha-synuclein membrane interactions. Here we reveal that dissociation of membrane-bound alpha-synuclein is dependent on brain-specific cytosolic proteins and insensitive to calcium or metabolic energy. Two PD-linked mutations (A30P and A53T) significantly increase the cytosol-dependent alpha-synuclein off-rate but have no effect on cytosol-independent dissociation. These results reveal a novel mechanism by which cytosolic brain proteins modulate alpha-synuclein interactions with intracellular membranes. Importantly, our finding that alpha-synuclein dissociation is up-regulated by both familial PD mutations implicates cytosolic cofactors in disease pathogenesis and as molecular targets to influence alpha-synuclein aggregation.
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
D'Souza, Cheryl
Kawarai, Toshitaka
St George-Hyslop, Peter
Westaway, David
Fraser, Paul
Tandon, Anurag
Language :
English
Title :
Cytosolic proteins regulate alpha-synuclein dissociation from presynaptic membranes.
Publication date :
2006
Journal title :
Journal of Biological Chemistry
ISSN :
0021-9258
eISSN :
1083-351X
Publisher :
American Society for Biochemistry and Molecular Biology, Baltimore, United States - Maryland
Volume :
281
Issue :
43
Pages :
32148-55
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
CIHR - Canadian Institutes of Health Research [CA] PSC - Parkinson Society Canada [CA] Fondation Léon Fredericq [BE]
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