title: Wnt/β-catenin signaling is required to rescue midbrain dopaminergic progenitors and promote neurorepair in ageing mouse model of Parkinson's disease.
abstract: Wnt/β-catenin signaling is required for specification and neurogenesis of midbrain dopaminergic (mDA) neurons, the pivotal neuronal population that degenerates in Parkinson's disease (PD), and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Wnt/β-catenin signaling plays a vital role in adult neurogenesis but whether it might engage DA neurogenesis/neurorepair in the affected PD brain is yet unresolved. Recently, the adult midbrain aqueduct periventricular regions (Aq-PVRs) were shown to harbor multipotent clonogenic neural stem/progenitor cells (mNPCs) with DA potential in vitro, but restrictive mechanisms in vivo are believed to limit their DA regenerative capacity. Using in vitro mNPC culture systems we herein demonstrate that aging is one most critical factor restricting mNPC neurogenic potential via dysregulation of Wnt/β-catenin signaling. Coculture paradigms between young/aged (Y/A) mNPCs and Y/A astrocytes identified glial age and a decline of glial-derived factors including Wnts as key determinants of impaired neurogenic potential, whereas Wnt activation regimens efficiently reversed the diminished proliferative, neuronal, and DA differentiation potential of A-mNPCs. Next, in vivo studies in wild (Wt) and transgenic β-catenin reporter mice uncovered Wnt/β-catenin signaling activation and remarkable astrocyte remodeling of Aq-PVR in response to MPTP-induced DA neuron death. Spatio-temporal analyses unveiled β-catenin signaling in predopaminergic (Nurr1(+)/TH(-)) and imperiled or rescuing DAT(+) neurons during MPTP-induced DA neuron injury and self-repair. Aging inhibited Wnt signaling, whereas β-catenin activation in situ with a specific GSK-3β antagonist promoted a significant degree of DA neurorestoration associated with reversal of motor deficit, with implications for neurorestorative approaches in PD.
authors.affiliation: Oasi Institute for Research on Mental Retardation and Brain Aging (IRCCS), Neuropharmacology Section, Troina, Enna, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: L'Episcopo
authors.forename: Cataldo
authors.initials: C
authors.lastname: Tirolo
authors.forename: Nunzio
authors.initials: N
authors.lastname: Testa
authors.forename: Salvatore
authors.initials: S
authors.lastname: Caniglia
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: D000375:Aging / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D018920:Coculture Techniques; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D008636:Mesencephalon / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058953:Neural Stem Cells / Q000378:metabolism*; D055495:Neurogenesis / Q000502:physiology*; D009457:Neuroglia / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism* / Q000503:physiopathology; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D060449:Wnt Signaling Pathway / Q000502:physiology*
keywords: Adult stem/neuroprogenitors; Aging; Dopaminergic plasticity; Neuroprotection; Neurorepair; Parkinson's disease; Wnt/β-catenin signaling