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

被引：78

作者：

Gordon, Richard ^{[1
,2
]}

Neal, Matthew L. ^{[1
]}

Luo, Jie ^{[1
]}

Langley, Monica R. ^{[1
]}

Harischandra, Dilshan S. ^{[1
]}

Panicker, Nikhil ^{[1
]}

Charli, Adhithiya ^{[1
]}

Jin, Huajun ^{[1
]}

Anantharam, Vellareddy ^{[1
]}

Woodruff, Trent M. ^{[2
]}

Zhou, Qun-Yong ^{[3
]}

Kanthasamy, Anumantha G. ^{[1
]}

Kanthasamy, Arthi ^{[1
]}

机构：

[1] Iowa State Univ, Dept Biomed Sci, Iowa Ctr Adv Neurotoxicol, Parkinson Disorders Res Program, Ames, IA 50011 USA

[2] Univ Queensland, Sch Biomed Sci, Brisbane, Qld 4072, Australia

[3] Univ Calif Irvine, Dept Pharmacol, Med Surge 2 363D, Irvine, CA 92697 USA

来源：

NATURE COMMUNICATIONS | 2016年 / 7卷

关键词：

KINASE-C-DELTA; OLFACTORY-BULB NEUROGENESIS; PROTEIN-COUPLED RECEPTORS; ENDOTHELIAL GROWTH-FACTOR; PARKINSONS-DISEASE; SUPRACHIASMATIC NUCLEUS; PROTEOLYTIC ACTIVATION; ANIMAL-MODELS; GENE-TRANSFER; CELL-CULTURE;

D O I：

10.1038/ncomms12932

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：18

共 58 条

[1] Inactivation of neuronal forebrain A2A receptors protects dopaminergic neurons in a mouse model of Parkinson's disease [J].