Influence of the amyloid oligomerization of the Parkinson's disease-related protein alpha-synuclein on its membrane-curvature sensitivity.

JAMESON DM; MAS C; CELEJ MS; AMBROGGIO EE; JAMES NG; GALLEA JI

Congreso; AVH-Kolleg, Current Advances on Neurodegeneration: form Molecular Biology to Translational Medicine; 2017

α-synulcein (AS) is a presynapticprotein extremely abundant in dopaminergic neurons where it participates in synaptic transmission acting as a criticalregulator of vesicle dynamics. The abnormal amyloidaggregation of AS is related to Parkinson's disease, a neurodegenerativemovement disorder associated with axon degenerationof dopaminergic nigral neurons. Prefibrillar soluble oligomers are pointed as neurotoxic species, since they might damagesynapses and dendrites by both altering the physiologicalfunction of AS and acting as active pathogenic species. In this scenario,AS-membrane interactions play a key role inmodulating AS physiopathology. The protein has a greater affinity for highly curved vesicles, such as that of synaptic vesicles.Therefore, we aimed at determining the loss of-function that might beassociated to the conversion of AS from its monomeric functional state to itspathological oligomeric form by evaluating the impactof AS oligomerization on its membrane curvature sensitivity. We usedFluorescence Correlation Spectroscopy to obtain quantitative information on the interaction between monomeric and oligomericAS and vesicles varying in sizes.Astonishingly, oligomeric AS also exhibits a higheraffinity for small unilamellar vesicles than for large unilamellar vesicles. Our findings provide further evidencefor the gain-of-function toxicity atributed toamyloid oligomeric species in Parkinson's disease and other synucleinopathies.