Cytosolic proteins regulate alpha-synuclein dissociation from presynaptic membranes
Authors: Anurag Tandon
David Westaway
Peter St George-Hyslop
Paul Fraser
Sabine Wislet-Gendebien
Toshitaka Kawarai
Cheryl D&#x27;Souza
Journal: Journal of Biological Chemistry (2006)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: alpha-synuclein; Lewy bodies; Parkinson disease; neuropathological trait; vesicular membranes
Affiliations: Centre for Research in Neurodegenerative Diseases, University of Toronto, 6 Queen's Park Crescent West, Toronto, Ontario M5S 3H2, Canada.

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. 

Retracted: Yes

PubPeer comments:
 Two images in figure 3 appear to overlap. Scale bars may also be incorrect. *** ![file] , 
 We are looking into this. , 
 There also appears to be a small area of overlap in 3A, perhaps due to cosmetic edits when relabeling the figure. *** Close up inverted ![file] *** ![file] , 
 21 July 2021 The authors have advised Figure 3 on page 8332 is incorrect. An error was made in the labelling of the images with some FLOM samples incorrectly labelled as FLOD samples. The authors inadvertently selected a mislabelled FLOM sample to represent the FLOD sample without realising both the FLOM and FLOD images were the same. The correct Figure 3 is shown in Download Article. ![file] The authors apologize for this error and advise that this does not affect the results of the paper. , 
 Inquiring minds are wondering whether the decision to accept a correction was made before or after co-author Thomas Webster left his editorial role at the journal. ,