Prokineticin-2 upregulation during neuronal injury mediates a compensatory protective response against dopaminergic neuronal degeneration

Richard Gordon, Matthew L. Neal, Jie Luo, Monica R. Langley, Dilshan S. Harischandra, Nikhil Panicker, Adhithiya Charli, Huajun Jin, Vellareddy Anantharam, Trent M. Woodruff, Qun-Yong Zhou, Anumantha G. Kanthasamy and Arthi Kanthasamy ()
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Richard Gordon: Parkinson Disorders Research Program, Iowa Center for Advanced Neurotoxicology, Iowa State University
Matthew L. Neal: Parkinson Disorders Research Program, Iowa Center for Advanced Neurotoxicology, Iowa State University
Jie Luo: Parkinson Disorders Research Program, Iowa Center for Advanced Neurotoxicology, Iowa State University
Monica R. Langley: Parkinson Disorders Research Program, Iowa Center for Advanced Neurotoxicology, Iowa State University
Dilshan S. Harischandra: Parkinson Disorders Research Program, Iowa Center for Advanced Neurotoxicology, Iowa State University
Nikhil Panicker: Parkinson Disorders Research Program, Iowa Center for Advanced Neurotoxicology, Iowa State University
Adhithiya Charli: Parkinson Disorders Research Program, Iowa Center for Advanced Neurotoxicology, Iowa State University
Huajun Jin: Parkinson Disorders Research Program, Iowa Center for Advanced Neurotoxicology, Iowa State University
Vellareddy Anantharam: Parkinson Disorders Research Program, Iowa Center for Advanced Neurotoxicology, Iowa State University
Trent M. Woodruff: School of Biomedical Sciences, The University of Queensland
Qun-Yong Zhou: 363D Med Surge 2, University of California
Anumantha G. Kanthasamy: Parkinson Disorders Research Program, Iowa Center for Advanced Neurotoxicology, Iowa State University
Arthi Kanthasamy: Parkinson Disorders Research Program, Iowa Center for Advanced Neurotoxicology, Iowa State University

Nature Communications, 2016, vol. 7, issue 1, 1-18

Abstract: Abstract Prokineticin-2 (PK2), a recently discovered secreted protein, regulates important physiological functions including olfactory biogenesis and circadian rhythms in the CNS. Interestingly, although PK2 expression is low in the nigral system, its receptors are constitutively expressed on nigrostriatal neurons. Herein, we demonstrate that PK2 expression is highly induced in nigral dopaminergic neurons during early stages of degeneration in multiple models of Parkinson’s disease (PD), including PK2 reporter mice and MitoPark mice. Functional studies demonstrate that PK2 promotes mitochondrial biogenesis and activates ERK and Akt survival signalling pathways, thereby driving neuroprotection. Importantly, PK2 overexpression is protective whereas PK2 receptor antagonism exacerbates dopaminergic degeneration in experimental PD. Furthermore, PK2 expression increased in surviving nigral dopaminergic neurons from PD brains, indicating that PK2 upregulation is clinically relevant to human PD. Collectively, our results identify a paradigm for compensatory neuroprotective PK2 signalling in nigral dopaminergic neurons that could have important therapeutic implications for PD.

Date: 2016
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DOI: 10.1038/ncomms12932

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