Reference : Cytosolic proteins regulate alpha-synuclein dissociation from presynaptic membranes.
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
http://hdl.handle.net/2268/1680
Cytosolic proteins regulate alpha-synuclein dissociation from presynaptic membranes.
English
Wislet-Gendebien, Sabine mailto [Université de Liège - ULg > 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 [> > > >]
2006
Journal of Biological Chemistry
American Society for Biochemistry and Molecular Biology
281
43
32148-55
Yes (verified by ORBi)
International
0021-9258
1083-351X
Baltimore
MD
[en] Animals ; Brain Chemistry ; Cytosol/chemistry ; Gene Expression Regulation ; Kinetics ; Mice ; Mice, Transgenic ; Parkinson Disease/genetics/metabolism ; Proteins/chemistry/genetics/metabolism ; Synaptic Membranes/metabolism ; Synaptosomes/metabolism ; Temperature ; Up-Regulation ; alpha-Synuclein/analysis/genetics/metabolism
[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.
Centre of research in neurodegenerative disease
Canadian Institute of Health Research (CIHR) ; Parkinson Society of Canada ; Leon Frederick Foundation
Researchers
http://hdl.handle.net/2268/1680
10.1074/jbc.M605965200

File(s) associated to this reference

Fulltext file(s):

FileCommentaryVersionSizeAccess
Open access
Wislet-Gendebien JBC 2006.pdfPublisher postprint620.76 kBView/Open

Bookmark and Share SFX Query

All documents in ORBi are protected by a user license.