title: Targeting Wnt signaling at the neuroimmune interface for dopaminergic neuroprotection/repair in Parkinson's disease.
abstract: 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.
authors.affiliation: OASI Institute for Research and Care on Mental Retardation and Brain Aging (IRCCS), Neuropharmacology Section, Via Conte Ruggero 73, 94018 Troina, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: L'Episcopo
authors.forename: Cataldo
authors.initials: C
authors.lastname: Tirolo
authors.forename: Salvo
authors.initials: S
authors.lastname: Caniglia
authors.forename: Nuccio
authors.initials: N
authors.lastname: Testa
authors.forename: Maria Concetta
authors.initials: MC
authors.lastname: Morale
authors.forename: Maria Francesca
authors.initials: MF
authors.lastname: Serapide
authors.forename: Stefano
authors.initials: S
authors.lastname: Pluchino
authors.forename: Bianca
authors.initials: B
authors.lastname: Marchetti
mesh_terms: D001921:Brain / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival; D060833:Cellular Microenvironment; D059290:Dopaminergic Neurons / Q000502:physiology*; D008954:Models, Biological; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009416:Nerve Regeneration / Q000235:genetics*; D015213:Neuroimmunomodulation / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism*
keywords: Parkinson's disease; Wnt/β-catenin signaling; dopaminergic neurons; neurodegeneration; neurogenesis; neuroinflammation; neuroprotection