Proceedings of The Physiological Society

Mitochondria: Form and function (London, UK) (2017) Proc Physiol Soc 38, C08

Oral Communications

Physiology and pathology of alpha-synuclein

M. Ludtmann1, P. Angelova1, M. Choi1, S. Gandhi1, A. Abramov1

1. Institute of Neurology, London, United Kingdom.

Alpha-synuclein aggregation and mitochondrial dysfunction are central to the pathogenesis of Parkinson's disease (PD). Despite a wealth of publications about misfolded α-synuclein in Parkinson's disease, very little has been reported about this protein's physiological function in health and the mechanism of its toxic gain of function in disease. This study establishes an important function for monomeric α-synuclein in the regulation of ATP synthase activity as application of extracellular monomeric α-synuclein shows that monomers enter the cell and localise to mitochondria, interact with ATP synthase and aids its efficiency (1). In Parkinson's disease, the monomer aggregates to form toxic oligomers, and we show that these aggregates maintain an interaction with the ATP synthase, a proposed key component of the mitochondrial permeability transition pore (mPTP). Oligomers, but not monomers, directly induce mPTP, and lower the threshold for calcium induced and ROS induced mPTP opening. Oligomeric α-synuclein is uniquely redox active and its ability to interact with ATP synthase and surrounding mitochondrial membranes, selectively oxidise its target. This targeted oxidation induces its conversion to form the mPTP leading to cell death which can be prevented by inhibition of the oligomer-induced oxidation events. This study highlights a physiological effect of monomers and the mechanism by which conformational changes (of α-synuclein) exert a toxic gain of function leading to neurodegeneration.

Where applicable, experiments conform with Society ethical requirements