| dc.contributor.advisor | Outeiro, Tiago Fleming Prof. Dr. | |
| dc.contributor.author | Xylaki, Maria | |
| dc.date.accessioned | 2022-06-14T13:58:30Z | |
| dc.date.available | 2022-06-21T00:50:12Z | |
| dc.date.issued | 2022-06-14 | |
| dc.identifier.uri | http://resolver.sub.uni-goettingen.de/purl?ediss-11858/14097 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-9275 | |
| dc.language.iso | eng | de |
| dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
| dc.subject.ddc | 570 | de |
| dc.title | The role of RNA in synapse physiology and neurodegeneration in models of Parkinson’s disease | de |
| dc.type | doctoralThesis | de |
| dc.contributor.referee | Outeiro, Tiago Fleming Prof. Dr. | |
| dc.date.examination | 2021-06-24 | de |
| dc.description.abstracteng | Synaptic 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 biomarkers. | de |
| dc.contributor.coReferee | Fischer, André Prof. Dr. | |
| dc.subject.eng | alpha-synuclein | de |
| dc.subject.eng | miRNA | |
| dc.subject.eng | synapse | |
| dc.identifier.urn | urn:nbn:de:gbv:7-ediss-14097-0 | |
| dc.affiliation.institute | Biologische Fakultät für Biologie und Psychologie | de |
| dc.subject.gokfull | Biologie (PPN619462639) | de |
| dc.description.embargoed | 2022-06-21 | de |
| dc.identifier.ppn | 180711855X | |
| dc.identifier.orcid | 0000-0002-7892-8621 | de |