Abstract
Parkinson’s disease is a neurodegenerative disorder characterized by the death of dopaminergic neurons and by accumulation of alpha-synuclein (aS) aggregates in the surviving neurons. The dopamine catabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) is a highly reactive and toxic molecule that leads to aS oligomerization by covalent modifications to lysine residues. Here we show that DOPAL-induced aS oligomer formation in neurons is associated with damage of synaptic vesicles, and with alterations in the synaptic vesicles pools. To investigate the molecular mechanism that leads to synaptic impairment, we first aimed to characterize the biochemical and biophysical properties of the aS-DOPAL oligomers; heterogeneous ensembles of macromolecules able to permeabilise cholesterol-containing lipid membranes. aS-DOPAL oligomers can induce dopamine leak in an in vitro model of synaptic vesicles and in cellular models. The dopamine released, after conversion to DOPAL in the cytoplasm, could trigger a noxious cycle that further fuels the formation of aS-DOPAL oligomers, inducing neurodegeneration.
Highlights
One relevant property of aS is its propensity to aggregate and to interact with DA20, leading to the formation of a heterogeneous ensemble of oligomers, which convert to amyloid fibrils that are deposited in LBs
Given (i) the annular shape of the aS-DOPAL oligomers observed by TEM (Fig. 5d) similar to those able to permeabilise lipid membranes[41] and (ii) the damages observed in synaptic vesicles in the experiments reported earlier in this manuscript, we investigated the ability of aS-DOPAL oligomers to permeabilise lipid membranes in vitro
The results suggest that the aS-DOPAL oligomers permeabilise the synaptic vesicles, and cause protons to leak out and raise the pH within the vesicles
Summary
One relevant property of aS is its propensity to aggregate and to interact with DA20, leading to the formation of a heterogeneous ensemble of oligomers, which convert to amyloid fibrils that are deposited in LBs. Different toxicity mechanisms, such as mitochondrial dysfunction[21], autophagy impairment[22] and membrane damage[23], have been ascribed to the diverse forms of aS aggregates reported in the literature[24] It is still unclear which are the most relevant aggregates for the pathology, and what their primary toxic effect may be. Starting from the detrimental effect caused by DOPAL-induced aS oligomerization on the function of synaptic vesicles, we investigated the structural and functional features of aS-DOPAL oligomers. This analysis allowed us to propose a mechanism by which synaptic vesicles could be damaged. We show that the oligomers can permeabilise cholesterol-containing lipid membranes mimicking synaptic vesicles in vitro, suggesting that the synergistic effect of aS and DOPAL accumulation in DA neurons may lead to the formation of oligomers able to negatively impact on the structure and function of synaptic vesicles
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