Cytosolic proteins regulate alpha-synuclein dissociation from presynaptic membranes. Export

@article{citeulike:4293887, abstract = {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.}, author = {Wislet-Gendebien, S. and D'Souza, C. and Kawarai, T. and St George-Hyslop, P. and Westaway, D. and Fraser, P. and Tandon, A.}, citeulike-article-id = {4293887}, citeulike-linkout-0 = {http://dx.doi.org/10.1074/jbc.M605965200}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/16926154}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=16926154}, day = {27}, doi = {10.1074/jbc.M605965200}, issn = {0021-9258}, journal = {The Journal of biological chemistry}, keywords = {pd, syn}, month = {October}, number = {43}, pages = {32148--32155}, posted-at = {2009-04-09 10:16:04}, priority = {2}, title = {Cytosolic proteins regulate alpha-synuclein dissociation from presynaptic membranes.}, url = {http://dx.doi.org/10.1074/jbc.M605965200}, volume = {281}, year = {2006} }

TY - JOUR ID - citeulike:4293887 L3 - citeulike-article-id:4293887 N2 - 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. IS - 43 JF - The Journal of biological chemistry SN - 0021-9258 EP - 32155 TI - Cytosolic proteins regulate alpha-synuclein dissociation from presynaptic membranes. VL - 281 SP - 32148 KW - pd KW - syn AU - Wislet-Gendebien, S AU - D'Souza, C AU - Kawarai, T AU - St George-Hyslop, P AU - Westaway, D AU - Fraser, P AU - Tandon, A PY - 2006/10/27/ UR - http://dx.doi.org/10.1074/jbc.M605965200 ER -