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Title: Dopamine (DA) Dependent Toxicity Relevant to DA Neuron Degeneration in Parkinson’s Disease (PD)
Authors: Zhou, Zhidong 
Thevapriya, Selvaratnam
Chao, Yin Xia
Lim, Tit Meng 
Tan, Eng King 
Keywords: Dopamine oxidation
Dopamine quinone
Parkinson’s disease
Reactive oxygen species
Issue Date: 2-Dec-2016
Publisher: Austin Publishing group
Citation: Zhou, Zhidong, Thevapriya, Selvaratnam, Chao, Yin Xia, Lim, Tit Meng, Tan, Eng King (2016-12-02). Dopamine (DA) Dependent Toxicity Relevant to DA Neuron Degeneration in Parkinson’s Disease (PD). Austin Journal of Drug Abuse and Addiction 3 (1) : 1010-1018. ScholarBank@NUS Repository.
Abstract: Parkinson’s disease (PD) is a common incurable neuron degenerative disease characterized by progressive dopamine (DA) neuron degeneration in the pars compacta of the substantia nigra (SN) plus Lewy body formation in affected brain areas. DA is the neuron transmitter for DA neurons and progressive DA neuron degeneration will significantly decrease DA content in SN, contributing to PD onset. DA can be catabolized to form inactivate metabolites by multiple enzymes accompanied with generation of reactive oxygen species (ROS). Furthermore DA is unstable and can undergo auto-oxidation or oxidation mediated enzymes or metal ions. The oxidation of DA can generate small molecular ROS and highly reactive DA quinones (DAQ). Accumulative evidence demonstrates that highly reactive DAQ seems to play more important pathological roles than small molecular ROS in DA neuron degeneration in PD. The small molecular ROS can induce oxidative stress in DA neurons via reversible oxidative modification of macromolecule including proteins, lipids and nucleic acids. However, DAQ is highly reactive and can induce DA neuron vulnerability via multiple toxic mechanisms. The DAQ can irreversibly and covalently conjugate with cysteine residues of proteins, leading to protein misfold, inactivation, and aggregation. Furthermore free DAQ and DAQ conjugated proteins can undergo redox cycling to generate deleterious ROS. We observe that endogenous DA derived DAQ can induce irreversible inhibition of ubiquitin-proteasome system (UPS). We also find that iron ions can significantly mediate DA oxidation and promote DAQ generation and subsequent toxicity to DA neurons. However conjugation of DAQ with proteins can be abrogated by sulfhydryl groups containing agents, including GSH and N-acetyl-cysteine (NAC). The toxicity of DAQ is also relevant to genetic factors induced DA neuron degeneration in familial form PD (FPD). The α-synuclein (α-syn) induced toxicity can be DA dependent. The conjugation of DAQ with α-syn can enhance α-syn toxicity. On the other hand, the mutations of PINK1 can up-regulate tyrosine hydroxylase (TH) and DA levels, leading to DA dependent DA neuron vulnerability and degeneration under PINK1 mutations. In summary, DA, especially DA derived DAQ, induced toxicity to DA neurons can be a centre event in PD onset and development. In this short review, some major previous achievements on DA dependent toxicity relevant to environmental and genetic factors induced DA neuron degeneration in PD have been summarized and discussed.
Source Title: Austin Journal of Drug Abuse and Addiction
Appears in Collections:Staff Publications

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