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Targeting Wnt signaling at the neuroimmune interface for dopaminergic neuroprotectionJrepair in Parkinson＇s disease

Journal of Molecular Cell Biology 2014年第1期8卷 13-26页

作者： Francesca L'Episcopo cataldo tirolo Salvo Caniglia Nuccio Testa Maria Concetta Moral~ Maria Francesca Serapide: Stefano Pluchino Bianca Marchetti OASI Institute for Research and Care on Mental Retardation and Brain Aging (IRCCS) Neuropharmacology Section Via Conte Ruggero 73 94018 Troina Italy Department of Physiolocal Sciences Medical School University of Catania Viale A. Doria 6 95125 Catania Italy Department of Clinical Neurosciences John van Geest Centre for Brain Repair and Wellcome Trust-Medical Research Counci~ Stem Celt Institute University ofCambridge Cambridge CB20PY UK Department of Clinical and Molecular Biomedicine Pharmacology Section Medical School University of Catania Viale A. Doria 6 95125 Catania Italy

During the past three decades, the Wingless-type MMTV integration site （Wnt） signaling cascade has emerged as an essential system regulating multiple processes in developing and adult brain. Accumulating evidence points to a dysregulation of Wnt signaling in major neurodegenerative pathologies including Parkinson＇s disease （PD）, a common neurodegenerative disorder characterized by the pro- gressive loss of midbrain dopaminergic （mDA） neurons and deregulated activation of astrocytes and microglia. This review highlights the emerging link between Wnt signaling and key inflammatory pathways during mDA neuron damage/repair in PD progression. In particular, we summarize recent evidence documenting that aging and neurotoxicant exposure strongly antagonize Wnt/β-catenin signaling in mDA neurons and subventricular zone （SVZ） neuroprogenitors via astrocyte-microglial interactions. Dysregulation of the crosstalk between Wnt/β-catenin signaling and anti-oxidant/anti-inflammatory pathways delineate novel mechanisms driving the decline of SVZ plasticity with age and the limited nigrostriatal dopaminergic self-repair in PD. These findings hold a promise in devetoping therapies that target Wnt/β-catenin signaling to enhance endogenous restoration and neuronal outcome in age-dependent diseases, such as PD.

关键词： Wnt/β-catenin signaling Parkinson's disease neuroinflammation dopaminergic neurons neurogenesis neurodegeneration neuroprotection

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