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L'Episcopo F.,OASI Institute for Research and Care on Mental Retardation and Brain Aging IRCCS | Tirolo C.,OASI Institute for Research and Care on Mental Retardation and Brain Aging IRCCS | Caniglia S.,OASI Institute for Research and Care on Mental Retardation and Brain Aging IRCCS | Testa N.,OASI Institute for Research and Care on Mental Retardation and Brain Aging IRCCS | And 5 more authors.
Journal of Molecular Cell Biology | Year: 2014

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 progressive 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 developing therapies that target Wnt/β-catenin signaling to enhance endogenous restoration and neuronal outcome in age-dependent diseases, such as PD. © 2014 The Author. Source


L'Episcopo F.,OASI Institute for Research and Care on Mental Retardation and Brain Aging IRCCS | Tirolo C.,OASI Institute for Research and Care on Mental Retardation and Brain Aging IRCCS | Testa N.,OASI Institute for Research and Care on Mental Retardation and Brain Aging IRCCS | Caniglia S.,OASI Institute for Research and Care on Mental Retardation and Brain Aging IRCCS | And 3 more authors.
Current Aging Science | Year: 2013

Parkinsons'disease (PD), a common neurodegenerative disorder, is characterized by progressive loss of dopaminergic (DAergic) neurons in the subtantia nigra pars compacta (SNpc) and gliosis. The cause and mechanisms underlying the demise of nigrostriatal DAergic neurons are not completely clarified, but interactions between genes and environmental factors are recognized to play a critical role in modulating the vulnerability to PD. Current evidence points to reactive glia as a pivotal factor in PD, but whether astroglia activation may protect or exacerbate DAergic neuron loss is presently the subject of much debate. Astrocytes and microglia are the key players in neuroinflammatory responses, by secreting an array of pro- and anti-inflammatory cytokines, anti-oxidant and neurotrophic factors. Here, the contribution of astrocytes and their ability to influence DAergic neurodegeneration, neuroprotection and neurorepair will be discussed. In particular, the dynamic interplay between astrocyte-derived factors and neurogenic signals in MPTP-induced plasticity of nigrostriatal DAergic neurons will be summarized together with recent findings showing that reactive astrocytes may contribute to promote DAergic neurogenesis from midbrain adult neural stem/precursor cells (NPCs). Within a host of astrocyte-derived factors, we unveiled Wingless-type MMTV integration site (Wnt)/β-catenin signalling was unveiled, as a strong candidate in MPTP-induced DAergic neuroplasticty/neurorepair. Understanding the intrinsic plasticity of nigrostriatal DAergic neurons and decifering the signals facilitating the crosstalk between astrocytes and midbrain neuroprogenitors may have implications for the role of stem cells technology in PD and for identifying potential therapeutic targets to promote endogenous neurorepair. © 2013 Bentham Science Publishers. Source

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