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Title: Mutant PINK1 upregulates tyrosine hydroxylase and dopamine levels, leading to vulnerability of dopaminergic neurons
Authors: Zhou, Zhidong 
Refai, Fathima Shaffra
Xie, Shao Ping
Ng, Shin Hui
Chan, Christine Hui Shan
Ho, Patrick Ghim Hoe
Zhang, Xiao Dong
Lim, Tit Meng 
Tan, Eng King 
Keywords: Dopamine
Parkinson disease
Tyrosine hydroxylase
Free radicals
Issue Date: Mar-2014
Publisher: Elsevier BV
Citation: Zhou, Zhidong, Refai, Fathima Shaffra, Xie, Shao Ping, Ng, Shin Hui, Chan, Christine Hui Shan, Ho, Patrick Ghim Hoe, Zhang, Xiao Dong, Lim, Tit Meng, Tan, Eng King (2014-03). Mutant PINK1 upregulates tyrosine hydroxylase and dopamine levels, leading to vulnerability of dopaminergic neurons. Free Radical Biology and Medicine 68 : 220-233. ScholarBank@NUS Repository.
Abstract: PINK1 mutations cause autosomal recessive forms of Parkinson disease (PD). Previous studies suggest that the neuroprotective function of wild-type (WT) PINK1 is related to mitochondrial homeostasis. PINK1 can also localize to the cytosol; however, the cytosolic function of PINK1 has not been fully elucidated. In this study we demonstrate that the extramitochondrial PINK1 can regulate tyrosine hydroxylase (TH) expression and dopamine (DA) content in dopaminergic neurons in a PINK1 kinase activity-dependent manner. We demonstrate that overexpression of full-length (FL) WT PINK1 can downregulate TH expression and DA content in dopaminergic neurons. In contrast, overexpression of PD-linked G309D, A339T, and E231G PINK1 mutations upregulates TH and DA levels in dopaminergic neurons and increases their vulnerability to oxidative stress. Furthermore transfection of FL WT PINK1 or PINK1 fragments with the PINK1 kinase domain can inhibit TH expression, whereas kinase-dead (KD) FL PINK1 or KD PINK1 fragments upregulate TH level. Our findings highlight a potential novel function of extramitochondrial PINK1 in dopaminergic neurons. Deregulation of these functions of PINK1 may contribute to PINK1 mutation-induced dopaminergic neuron degeneration. However, deleterious effects caused by PINK1 mutations may be alleviated by iron-chelating agents and antioxidant agents with DA quinone-conjugating capacity. © 2014 Published by Elsevier Inc.
Source Title: Free Radical Biology and Medicine
ISSN: 0891-5849
Appears in Collections:Staff Publications

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