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

R. Gordon,Matthew L. Neal,Jie Luo,Monica R. Langley,Dilshan S. Harischandra,Nikhil Panicker,Adhithiya Charli,Huajun Jin,V. Anantharam,T. Woodruff,Q. Zhou,A. Kanthasamy,A. Kanthasamy

Published 2016 in Nature Communications

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. Prokineticin-2 (PK2) is a secreted protein involved in a number of physiological functions. Here, the authors find that PK2 expression increases in surviving DA neurons from Parkinson's disease patients, and show it protects against dopaminergic degeneration in PD mouse models.

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