The Cytotoxic Effect of α‐Synuclein Aggregates

Parkinson's disease is a neurodegenerative disorder involving a functional protein, α‐synuclein, whose primary function is related to vesicle trafficking. However, α‐synuclein is prone to form aggregates, and these inclusions, known as Lewy bodies, are the hallmark of Parkinson's disease. α‐synuclein can alter its conformation and acquire aggregating capacity, forming aggregates containing β‐sheets. This protein's pathogenic importance is based on its ability to form oligomers that impair synaptic transmission and neuronal function by increasing membrane permeability and altering homeostasis, generating a deleterious effect over cells. First, we establish that oligomers interfere with the mechanical properties of 1,2‐dioleoyl‐sn‐glycero‐3‐phosphocholine (DOPC) membrane, as demonstrated by nanoindentation curves. In contrast, nanoindentation revealed that the α‐synuclein monomer's presence leads to a much more resistant lipid bilayer. Moreover, the oligomers’ interaction with cell membranes can promote lactate dehydrogenase (LDH) release, suggesting the activation of cytotoxic events. Aggregates toxicity: In the present work, we show that after monomer binding to DOPC, the membrane is stabilized, as demonstrated by nanoindentation techniques. However, once DOPC is incubated in α‐synuclein oligomers’ presence, the membrane is weakened due to interactions with aggregates. The picture illustrates cell membrane disruption induced by α‐synuclein oligomers and subsequent LDH release.