α-Synuclein Membrane Association Is Regulated by the Rab3a Recycling Machinery and Presynaptic Activity*

Abstract

Background: ␣-Synuclein is known to undergo exchange between membrane and cytosolic compartments. Results: ␣-Synuclein interacts with GTP-bound Rab3a on synaptic vesicles, and its dissociation is mediated by GDI/Hsp90. Conclusion: ␣-Synuclein's membrane association and dissociation cycle is linked to synaptic activity by the Rab3a recycling machinery. Significance: Significance: Impairments to ␣-synuclein interactions with vesicles and with the Rab3a recycling machinery may affect neurodegeneration.

Synaptic proteins predict cognitive decline in Alzheimer's disease and Lewy body dementia

“…Interestingly, the Rab3A recycling machinery is closely linked to synuclein's membrane association and dissociation cycle known to increase α-synuclein sequestration leading to cognitive consequences [36]. Our results presenting associations between Rab3A and synuclein pathology are in line with previous findings reporting increased binding of Rab3A to alphasynuclein aggregates in DLB [37], proposing that decreased Rab3A levels, is likely to directly affect not only the reserve synaptic vesicle pool but alpha-synuclein pathology as well.…”

Synaptic Vesicle-Recycling Machinery Components as Potential Therapeutic Targets

“…Rab3A also associates with pathologic a-synuclein in a GTPdependent manner (Dalfó et al, 2004;Dalfó and Ferrer, 2005;Chen et al, 2013b). Specific GTPase inhibitors may be a possible mechanism to modulate rab3A activity.…”

New insights into cellular α-synuclein homeostasis in health and disease

“…It is also possible that tetramers and related multimers can dissociate from membranes only when one or a few lipids remain/become bound to the multimers as a cofactor to stabilize the multimeric structure [53]. Additionally, cytosolic factors or synaptic activity itself may trigger the switch from membranebound to cytosolic forms of aSyn [54,55].…”