Journal
JOURNAL OF NEUROSCIENCE
Volume 32, Issue 6, Pages 2062-2085Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.5259-11.2012
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Funding
- Italian Ministry of Health [82, 56, GR08-7]
- Italian Ministry of Research
- Italian Multiple Sclerosis Foundation [2004/R/15, 2010/R/31]
- National Multiple Sclerosis Society [RG-4001-A1]
- Italian Ministry of Research and University
- Wings for Life [XBAG/163]
- Banca Agricola Popolare di Ragusa
- OASI (IRCCS) Institution for Research and Care on Mental Retardation and Brain Aging
- European Research Council [260511-SEM_SEM]
- John and Lucille van Geest Trust
- MRC [G0800784] Funding Source: UKRI
- Medical Research Council [G0800784B, G0800784] Funding Source: researchfish
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In Parkinson's disease (PD), neurogenesis is impaired in the subventricular zone (SVZ) of postmortem human PD brains, in primate nonhuman and rodent models of PD. The vital role of Wingless-type MMTV integration site (Wnt)/beta-catenin signaling in the modulation of neurogenesis, neuroprotection, and synaptic plasticity coupled to our recent findings uncovering an active role for inflammation and Wnt/beta-catenin signaling in MPTP-induced loss and repair of nigrostriatal dopaminergic (DAergic) neurons prompted us to study the impact of neuroinflammation and the Wnt/beta-catenin pathway in the response of SVZ neuroprogenitors (NPCs) in MPTP-treated mice. In vivo experiments, using bromodeoxyuridine and cell-specific markers, and ex vivo time course analyses documented an inverse correlation between the reduced proliferation of NPCs and the generation of new neuroblasts with the phase of maximal exacerbation of microglia reaction, whereas a shift in the microglia proinflammatory phenotype correlated with a progressive NPC recovery. Ex vivo and in vitro experiments using microglia NPC coculture paradigms pointed to NADPH-oxidase (gpPHOX(91)), a major source of microglial ROS, and reactive nitrogen species as candidate inhibitors of NPC neurogenic potential via the activation of glycogen synthase 3 (pGSK-3 beta(Tyr216) leading to loss of beta-catenin, a chief downstream transcriptional effector. Accordingly, MPTP/MPP+ (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) caused beta-catenin downregulation and pGSK-3 beta(Tyr216) overexpression, whereas manipulation of Wnt/beta-catenin signaling with RNA interference-mediated GSK-3 beta knockdown or GSK-3 beta antagonism reversed MPTP-induced neurogenic impairment ex vivo/in vitro or in vivo. Reciprocally, pharmacological modulation of inflammation prevented beta-catenin downregulation and restored neurogenesis, suggesting the possibility to modulate this endogenous system with potential consequences for DAergic neuroprotection and self-repair.
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