Cytosolic proteins regulate alpha-synuclein dissociation from presynaptic membranes.
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.
Wislet-Gendebien
Sabine
S
Centre for Research in Neurodegenerative Diseases, University of Toronto, 6 Queen's Park Crescent West, Toronto, Ontario M5S 3H2, Canada.
D'Souza
Cheryl
C
Kawarai
Toshitaka
T
St George-Hyslop
Peter
P
Westaway
David
D
Fraser
Paul
P
Tandon
Anurag
A
D000818:Animals; D001923:Brain Chemistry; D003600:Cytosol / Q000737:chemistry*; D005786:Gene Expression Regulation; D007700:Kinetics; D051379:Mice; D008822:Mice, Transgenic; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013570:Synaptic Membranes / Q000378:metabolism*; D013574:Synaptosomes / Q000378:metabolism*; D013696:Temperature; D015854:Up-Regulation; D051844:alpha-Synuclein / Q000032:analysis / Q000235:genetics / Q000378:metabolism*
D011506:Proteins; D051844:alpha-Synuclein