| dc.contributor.advisor | Kügler, Sebastian Dr. | |
| dc.contributor.author | Psol, Maryna | |
| dc.date.accessioned | 2019-06-14T08:21:04Z | |
| dc.date.available | 2019-06-14T08:21:04Z | |
| dc.date.issued | 2019-06-14 | |
| dc.identifier.uri | http://hdl.handle.net/21.11130/00-1735-0000-0003-C133-9 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-7505 | |
| dc.language.iso | eng | de |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | |
| dc.subject.ddc | 570 | de |
| dc.title | Neurotoxicity and aggregation of β-synuclein and its P123H and V70M mutants associated with dementia with Lewy bodies | de |
| dc.type | doctoralThesis | de |
| dc.contributor.referee | Outeiro, Tiago Fleming Prof. Dr. | |
| dc.date.examination | 2018-06-26 | |
| dc.description.abstracteng | Dementia with Lewy bodies is a progressive degenerative brain disorder which accounts for 7 to 25% of all dementia cases. Two rare missense mutations of β-synuclein, P123H and V70M were identified in familial and sporadic cases of DLB, respectively. Some previous publications showed that P123H and V70M mutations may contribute to the DLB pathology by aggregation (Janowska et al., 2016), inducing neurodegeneration (Fujita et al., 2010) or causing lysosomal pathology (Wei et al., 2007). Still, their pathological roles were not clearly understood at the beginning of this project. Here, neurotoxicity and aggregation of WT-βS and its mutants, P123H-βS and V70M-βS, were studied in vitro in primary cultured cortical neurons and in vivo in dopaminergic neurons of SNpc of rat. V70M-βS was described for the first time in an in vivo model.
It was found that the V70M mutation in several conditions aggravated pathologic effects of WT-βS, namely, V70M-βS:
increased cell loss in primary cortical neurons; induced more condensation of mitochondria in cultured neurons;
caused more pronounced loss of nigrostriatal projections and formation of axonal bulbs in rats striata;
showed less fibril formation in cultured neurons and in vivo in Substantia nigra.
Increase in mitochondrial deformations under influence of V70M may have been an early cellular mechanism leading to the cell death. Moreover, increased neurotoxicity in primary cortical neurons correlated with lower resistance of V70M to PK digestion; this may indicate lower extent of V70M-βS fibril formation and increase in amount of “toxic oligomeric species”.
Altogether, these data indicate pathologic role of V70M mutation of βS and its putative relevance to DLB pathogenesis.
The P123H mutation did not contribute to the pathological features of WT-βS in any of the experiments of this Ph.D. project, which may indicate that it is coincidential to DLB pathology. However, further investigation of P123H-βS with respect to its long-term effects in different experimental models may be necessary to exclude its possible pathological role in DLB. | de |
| dc.contributor.coReferee | Zweckstetter, Markus Prof. Dr. | |
| dc.subject.eng | Neurotoxicity, aggregation, β-synuclein, P123H, V70M, dementia with Lewy bodies, Parkinson's disease, AAV, mitochondria, Proteinase K | de |
| dc.identifier.urn | urn:nbn:de:gbv:7-21.11130/00-1735-0000-0003-C133-9-3 | |
| dc.affiliation.institute | Göttinger Graduiertenschule für Neurowissenschaften, Biophysik und molekulare Biowissenschaften (GGNB) | de |
| dc.subject.gokfull | Biologie (PPN619462639) | de |
| dc.identifier.ppn | 1667487337 | |