title: Prokineticin-2 upregulation during neuronal injury mediates a compensatory protective response against dopaminergic neuronal degeneration.
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.
authors.affiliation: Parkinson Disorders Research Program, Iowa Center for Advanced Neurotoxicology, Department of Biomedical Sciences, Iowa State University, Ames, Iowa 50011, USA.|School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Richard
authors.identifier: 0000-0003-2478-4607
authors.initials: R
authors.lastname: Gordon
authors.affiliation: Parkinson Disorders Research Program, Iowa Center for Advanced Neurotoxicology, Department of Biomedical Sciences, Iowa State University, Ames, Iowa 50011, USA.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Neal
authors.affiliation: Parkinson Disorders Research Program, Iowa Center for Advanced Neurotoxicology, Department of Biomedical Sciences, Iowa State University, Ames, Iowa 50011, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Luo
authors.affiliation: Parkinson Disorders Research Program, Iowa Center for Advanced Neurotoxicology, Department of Biomedical Sciences, Iowa State University, Ames, Iowa 50011, USA.
authors.forename: Monica R
authors.initials: MR
authors.lastname: Langley
authors.affiliation: Parkinson Disorders Research Program, Iowa Center for Advanced Neurotoxicology, Department of Biomedical Sciences, Iowa State University, Ames, Iowa 50011, USA.
authors.forename: Dilshan S
authors.identifier: 0000-0003-3220-8765
authors.initials: DS
authors.lastname: Harischandra
authors.affiliation: Parkinson Disorders Research Program, Iowa Center for Advanced Neurotoxicology, Department of Biomedical Sciences, Iowa State University, Ames, Iowa 50011, USA.
authors.forename: Nikhil
authors.initials: N
authors.lastname: Panicker
authors.affiliation: Parkinson Disorders Research Program, Iowa Center for Advanced Neurotoxicology, Department of Biomedical Sciences, Iowa State University, Ames, Iowa 50011, USA.
authors.forename: Adhithiya
authors.initials: A
authors.lastname: Charli
authors.affiliation: Parkinson Disorders Research Program, Iowa Center for Advanced Neurotoxicology, Department of Biomedical Sciences, Iowa State University, Ames, Iowa 50011, USA.
authors.forename: Huajun
authors.initials: H
authors.lastname: Jin
authors.affiliation: Parkinson Disorders Research Program, Iowa Center for Advanced Neurotoxicology, Department of Biomedical Sciences, Iowa State University, Ames, Iowa 50011, USA.
authors.forename: Vellareddy
authors.initials: V
authors.lastname: Anantharam
authors.affiliation: School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Trent M
authors.identifier: 0000-0003-1382-911X
authors.initials: TM
authors.lastname: Woodruff
authors.affiliation: Department of Pharmacology, 363D Med Surge 2, University of California, Irvine, California 92697, USA.
authors.forename: Qun-Yong
authors.initials: QY
authors.lastname: Zhou
authors.affiliation: Parkinson Disorders Research Program, Iowa Center for Advanced Neurotoxicology, Department of Biomedical Sciences, Iowa State University, Ames, Iowa 50011, USA.
authors.forename: Anumantha G
authors.initials: AG
authors.lastname: Kanthasamy
authors.affiliation: Parkinson Disorders Research Program, Iowa Center for Advanced Neurotoxicology, Department of Biomedical Sciences, Iowa State University, Ames, Iowa 50011, USA.
authors.forename: Arthi
authors.initials: A
authors.lastname: Kanthasamy
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D016923:Cell Death; D002490:Central Nervous System / Q000166:cytology*; D059290:Dopaminergic Neurons / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005768:Gastrointestinal Hormones / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D013378:Substantia Nigra / Q000166:cytology
chemical_list: D005768:Gastrointestinal Hormones; D009479:Neuropeptides; C486586:Prok2 protein, mouse; D011994:Recombinant Proteins; D048049:Extracellular Signal-Regulated MAP Kinases