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Alpha-synuclein-associated alterations at the synapse in models of Parkinson’s disease

dc.contributor.advisorOuteiro, Tiago Fleming Prof. Dr.
dc.contributor.authorPires dos Santos, Patrícia
dc.format.extent180 Seitende
dc.titleAlpha-synuclein-associated alterations at the synapse in models of Parkinson’s diseasede
dc.contributor.refereeRizzoli, Silvio O. Prof. Dr.
dc.description.abstractengParkinson’s disease (PD) is one of the most common neurodegenerative disorders that is characterized by the typical motor features, and also by a multiplicity of non-motor symptoms. The main pathological hallmarks of PD are a progressive, and profound, loss of dopaminergic neurons in the substantia nigra, as well as the accumulation of protein inclusions rich in the protein alpha-synuclein (aSyn). Yet, the exact molecular mechanisms linking aSyn to PD remain unknown. Despite the fact that aSyn is involved in producing synaptic vesicles (SVs) and their transport, in SNARE complex assembly, and in modulating synaptic functions, the effect of aSyn accumulation at the synapses remains unclear. Therefore, we sought to investigate the link between the overexpression of aSyn and the major aSyn-related alterations in the synapse. In our study, we exposed primary hippocampal neurons to recombinant aSyn species, or to aSyn overexpression using a lentiviral vector encoding for aSyn, and systematically analysed the effects on presynaptic function. Although the neurons exhibited a robust expression of aSyn, aSyn did not result in a direct effect on neurotoxicity, in a change in synaptic protein levels, in dendrite length, or in spontaneous neuronal activity. We used a differential ultracentrifugation protocol to purify SVs from 3-month-old transgenic mice overexpressing human wild-type aSyn (WTaSyn) and from control wild-type (WT) mice and provided a proteomic and functional characterization of these vesicles. The proteomic analysis of SVs from both animals revealed specific protein composition and pathways enrichment. Furthermore, we analysed the synaptic protein levels in the brains of Tg and WT mice and we did not observe any significant changes. These results were consistent with the results from the cellular model. Finally, we quantified the aSyn levels in several biofluids from 3 m.o, 6 m.o and 9 m.o old transgenic mice overexpressing A30P mutant aSyn (A30PaSyn), WTaSyn, and WT. Interestingly, serum and plasma aSyn levels were increased in A30PaSyn mice when compared to age-matched controls for the three-time points, suggesting that serum and plasma aSyn could be a reliable biomarker to distinguish PD from healthy controls. Overall, our work indicates that even if the levels of aSyn are increased, affecting the protein composition and/or biological processes associated with SVs, in the end, overexpression of the protein does not, per se, induce significant synaptic dysfunction in the models used. A clear understanding of the precise mechanisms that correlate some biological effects of neurodegeneration with the accumulation of specific aSyn species is fundamental for understanding the molecular underpinnings of PD. Overcoming the limitations that have hampered the identification of these mechanisms can contribute to the improvement of diagnostic accuracy and the development of novel targets for therapeutic intervention in PD and other
dc.contributor.coRefereeBrose, Nils Prof. Dr.
dc.contributor.thirdRefereeStadelmann-Nessler, Christine Prof. Dr.
dc.contributor.thirdRefereeBraus, Gerhard Prof. Dr.
dc.contributor.thirdRefereeGoya-Maldonado, Roberto PD Dr.
dc.subject.gerneurodegenerative diseasesde
dc.subject.gerParkinson's diseasede
dc.subject.germodels of Parkinson's diseasede
dc.subject.gersynaptic vesiclesde
dc.subject.engneurodegenerative diseasesde
dc.subject.engParkinson's diseasede
dc.subject.engmodels of Parkinson's diseasede
dc.subject.engsynaptic vesiclesde
dc.affiliation.instituteMedizinische Fakultät
dc.subject.gokfullMedizin (PPN619874732)de
dc.notes.confirmationsentConfirmation sent 2023-08-16T19:45:01de

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