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The role of RNA in synapse physiology and neurodegeneration in models of Parkinson’s disease

dc.contributor.advisorOuteiro, Tiago Fleming Prof. Dr.
dc.contributor.authorXylaki, Maria
dc.titleThe role of RNA in synapse physiology and neurodegeneration in models of Parkinson’s diseasede
dc.contributor.refereeOuteiro, Tiago Fleming Prof. Dr.
dc.description.abstractengSynaptic dysfunction is an early alteration in multiple neurodegenerative disorders. Parkinson’s disease (PD) is characterised by the accumulation of α-synuclein (αsyn) in pathological inclusions known as Lewy bodies and Lewy neurites. αsyn is involved in synaptic vesicle trafficking, and SNARE complex formation at the nerve terminals. In pathological conditions, it is associated with alterations of synaptic function. Interestingly, αsyn also occurs in the nucleus where it induces epigenetic changes. RNA-mediated processes contribute to synaptic remodelling by RNA translocation to the synaptic compartment. This is particularly relevant for microRNAs (miRNAs) that can regulate mRNA expression by complementary binding. Here, we sought to identify miRNAs associated with synaptic processes that may contribute to synapse degeneration. We performed small RNA-Sequencing of the midbrain of 6-month-old transgenic mice expressing A30P mutant αsyn, present in familial forms of PD. Gene ontology (GO) functional annotation and pathway analysis of differentially expressed genes and miRNAs revealed several deregulated biological processes linked with the synaptic compartment. A negative correlation between deregulated miRNAs and gene targets highlighted the top interacting miRNAs and identified miR-101a-3p as a prominent regulator of synaptic plasticity. MiR-101a-3p was validated by qPCR in the transgenic mouse midbrain and in the cortex of Dementia with Lewy Bodies (DLB) patients. Confocal imaging of primary cortical neurons overexpressing miR-101a-3p showed reduced dendritic length and altered spine morphology. Further correlation with synaptic plasticity was provided by wild-type mice exposed to enriched environment which showed reduced levels of miR-101a-3p. Finally, exposure of primary cortical neurons to recombinant αsyn species showed a direct effect of αsyn on miR-101a-3p levels. Our data support the emerging role of specific microRNAs as key regulators of gene expression alterations associated with αsyn. Identification of RNA based processes leading to synaptic compromise may reveal novel targets for therapeutic intervention in synucleinopathies, and may also result in the development of novel
dc.contributor.coRefereeFischer, André Prof. Dr.
dc.subject.engalpha-synuclein; miRNA; synapsede
dc.affiliation.instituteBiologische Fakultät für Biologie und Psychologiede
dc.subject.gokfullBiologie (PPN619462639)de

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