THESIS
2021
1 online resource (xii, 141 pages) : illustrations (some color)
Abstract
Parkinson’s disease (PD) is a common neurodegenerative disorder that is primarily sporadic,
but familial-linked PD cases have also been found. The first reported gene mutation linked to
PD is α-synuclein (α-syn). Studies have shown that mutations, increased expression, or
abnormal processing of α-syn contribute to PD, but it is believed that multiple mechanisms are
involved. One of the contributing factors is post-translational modification such as
phosphorylation of α-syn at Ser129 by G-protein-coupled receptor kinases (GRKs), casein
kinase 2 (CK2), and polo-like kinase 2 (PLK2). Another crucial contributing factor to PD
pathogenesis is oxidative and nitrosative stress. In this study, I found that GRK6 and CK2 can
be S-nitrosylated by nitric oxide (NO) both in vitro and in vivo. S-nit...[
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Parkinson’s disease (PD) is a common neurodegenerative disorder that is primarily sporadic,
but familial-linked PD cases have also been found. The first reported gene mutation linked to
PD is α-synuclein (α-syn). Studies have shown that mutations, increased expression, or
abnormal processing of α-syn contribute to PD, but it is believed that multiple mechanisms are
involved. One of the contributing factors is post-translational modification such as
phosphorylation of α-syn at Ser129 by G-protein-coupled receptor kinases (GRKs), casein
kinase 2 (CK2), and polo-like kinase 2 (PLK2). Another crucial contributing factor to PD
pathogenesis is oxidative and nitrosative stress. In this study, I found that GRK6 and CK2 can
be S-nitrosylated by nitric oxide (NO) both in vitro and in vivo. S-nitrosylation of GRK6 and
CK2 enhanced their kinase activity towards the phosphorylation of α-syn at Ser129. In an A53T
α-syn transgenic mouse model of PD, I found that increased GRK6 and CK2 S-nitrosylation
were observed in an age-dependent manner, and it was associated with an increased level of
pSer129 α-syn. Deleting neuronal nitric oxide synthase in A53T α-syn transgenic mice reduced
the levels pSer129 α-syn and α-syn in an age-dependent manner. The results provide a novel
mechanism of how NO through S-nitrosylation of GRK6 and CK2 can enhance the
phosphorylation of pSer129 α-syn and contribute to PD pathogenesis in the context of aging.
On the other hand, PLK2 mediated α-syn degradation through the autophagy-lysosomal
pathway by phosphorylating α-syn at Ser129. I reported that inhibition of the ubiquitin-proteasomal
pathway causes the accumulation of PLK2 and enhanced degradation of α-syn. By
administrating a low dosage of Proteasome Inhibitor I, the level of soluble and insoluble α-syn
in A53T α-syn transgenic mice dropped to its half. The modulation of α-syn phosphorylation
can hence be a possible target in searching for treatment of PD.
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