THESIS
2021
1 online resource (xi, 87 pages) : illustrations (some color)
Abstract
Parkinson’s disease (PD) is a common neurodegenerative disease around the world. Formation
of Lewy bodies is one of the hallmarks of PD pathogenesis. α-synuclein (α-syn) is the major
component of Lewy bodies and its degradation is considered as a potential therapeutic
approach of PD. Polo-like kinase 2 (PLK2) is a kinase that phosphorylates α-syn at Ser129 site
and its level is regulated by ubiquitin-proteasome system (UPS). The PLK2 is reported to
induce α-syn degradation through a phosphorylation-dependent pathway and the raised levels
of PLK2 increases the level of pSer129 α-syn together with a decreased α-syn level. In HEK
293T, SH-SY5Y cells and primary culture of mouse cortical neurons, the PLK2 and pSer129
α-syn levels were significantly increased upon proteasomal inhibition foll...[
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Parkinson’s disease (PD) is a common neurodegenerative disease around the world. Formation
of Lewy bodies is one of the hallmarks of PD pathogenesis. α-synuclein (α-syn) is the major
component of Lewy bodies and its degradation is considered as a potential therapeutic
approach of PD. Polo-like kinase 2 (PLK2) is a kinase that phosphorylates α-syn at Ser129 site
and its level is regulated by ubiquitin-proteasome system (UPS). The PLK2 is reported to
induce α-syn degradation through a phosphorylation-dependent pathway and the raised levels
of PLK2 increases the level of pSer129 α-syn together with a decreased α-syn level. In HEK
293T, SH-SY5Y cells and primary culture of mouse cortical neurons, the PLK2 and pSer129
α-syn levels were significantly increased upon proteasomal inhibition following by the
decrease in α-syn levels. Although autophagy was reported to be responsible for the PLK2
induced α-syn degradation, the PLK2, pSer129 α-syn and α-syn levels were not rescued by
autophagic inhibition. Interestingly, the co-treatments of proteasome and autophagy inhibitors
resulted in even lower pSer129 α-syn and α-syn levels in HEK 293T and SH-SY5Y cells.
Pathways other than UPS and autophagy may be involved in the PLK2 induced α-syn
degradation.
New mouse models that conditionally express human α-syn or α-syn-CL1 were created by
applying Cre-loxP approach. The expressions of α-syn or α-syn-CL1 were achieved in different
parts of brains by crossbreeding the mouse models with Nestin
Cre mouse line. In addition, the
dopaminergic neuronal loss was also observed in those mice expressing α-syn-CL1. Therefore,
other hallmarks of PD pathogenesis such as motor symptoms, formation of Lewy bodies and
dopamine levels may be further revealed in these mouse models to evaluate their abilities in
mimicking PD pathogenesis.
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