Reactive astrocytes and Wnt/β-catenin signaling link nigrostriatal injury to repair in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease

L’Episcopo, Francesca; Tirolo, Cataldo; Testa, Nuccio; Caniglia, Salvatore; Morale, Maria Concetta; Cossetti, Chiara; D’Adamo, Patrizia; Zardini, Elisabetta; Andreoni, Laura; Ihekwaba, Adaoha E. C.; Serra, Pier Andrea; Franciotta, Diego; Martino, Gianvito; Pluchino, ﻿Stefano; Marchetti, Bianca

doi:10.1016/j.nbd.2010.10.023

Cited by 171 publications

(413 citation statements)

References 106 publications

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“…Furthermore, administration of THP once weekly for 2 weeks to MPTP-treated mice is reported to restore positive cells for tyrosine hydroxylase in the substantia nigra as well as motor behavior, and to induce the generation of new positive neurons for tyrosine hydroxylase in the substantia nigra [53]. In this study, THP was administered at a time when the damage induced by MPTP is stable, that is after 7 days [54]. Thus, THP has a potent capacity for recovery and neurogenesis of tyrosine hydroxylase neurons.…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective Effect of Progesterone in MPTP-Treated Male Mice

et al. 2015

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Background: Numerous studies have reported on the neuroprotective activity of estradiol, whereas the effect of the other ovarian steroid, progesterone, is much less documented. Methods: This study sought to investigate neuroprotection with a low dose of progesterone (1 µg) in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated male mice to model Parkinson's disease and compare it to the effect of this steroid in intact mice (experiment 1). We also investigated if high doses of progesterone could protect dopaminergic neurons already exposed to MPTP (experiment 2). We measured progesterone effects on various dopaminergic markers [dopamine and its metabolites, dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2)] and on neuroactive steroids in both plasma and the brain. Results: For experiment 1, our results showed that progesterone completely prevented the effect of MPTP toxicity on dopamine concentrations, on the increase in the 3-methoxytyramine/dopamine ratio, as well as on VMAT2-specific binding in the striatum and the substantia nigra. Progesterone decreased MPTP effects on 3,4-dihydroxyphenylacetic acid concentrations and DAT-specific binding in the lateral part of the anterior striatum and in the middle striatum (medial and lateral parts). Progesterone treatment of intact mice had no effect on the markers investigated. For experiment 2, measures of dopaminergic markers in the striatum showed that 8 mg/kg of progesterone was the most effective dose to reduce MPTP effects, and more limited effects were observed with 16 mg/kg. We found that progesterone treatment increases the levels of brain progesterone itself as well as of its metabolites. Conclusion: Our result showed that progesterone has neuroprotective effects on dopaminergic neurons in MPTP-treated male mice.

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Section: Discussionmentioning

confidence: 99%

Neuroprotective Effect of Progesterone in MPTP-Treated Male Mice

et al. 2015

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“…35,36 Such non-neuronal cells of the CNS have been shown to be instrumental in orchestrating pathways involved in both repair, and in exacerbating neuronal injury, when oxidative stress is present. Ageing and disease onset may decrease microglial/astrocytes function, with such cells loosing the ability to repress GSK-3β activation through decreased Wnt-1 signaling, resulting in the loss of stabilized nuclear β-catenin and subsequent loss of the induction of neural protective β-catenin-specific gene expression programs.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have shown that GSK-3β is an important mediator in the injury and repair processes of neurons during cross-talk between DA-neurons and reactive astrocytes. 35,36 These studies showed that astrocyte-derived Wnt1 was capable of blocking GSK-3β activation, allowing the nuclear accumulation of β-catenin and subsequent gene expression of β-catenin-dependent targets essential for neuron survival and repair during chemical or metabolic insults. The importance of regulating the active/ inactive states of GSK-3β in regard to neuronal stability is further supported through the analysis of conditional (Tetinducible) transgenic mice expressing a dominant-negative GSK-3β-K85R mutant or expressing the GSK-3β-S9A mutant.…”

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confidence: 99%

GSK-3β dysregulation contributes to parkinson’s-like pathophysiology with associated region-specific phosphorylation and accumulation of tau and α-synuclein

et al. 2014

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Aberrant posttranslational modifications (PTMs) of proteins, namely phosphorylation, induce abnormalities in the biological properties of recipient proteins, underlying neurological diseases including Parkinson's disease (PD). Genome-wide studies link genes encoding α-synuclein (α-Syn) and Tau as two of the most important in the genesis of PD. Although several kinases are known to phosphorylate α-Syn and Tau, we focused our analysis on GSK-3β because of its accepted role in phosphorylating Tau and to increasing evidence supporting a strong biophysical relationship between α-Syn and Tau in PD. Therefore, we investigated transgenic mice, which express a point mutant (S9A) of human GSK-3β. GSK-3β-S9A is capable of activation through endogenous natural signaling events, yet is unable to become inactivated through phosphorylation at serine-9. We used behavioral, biochemical, and in vitro analysis to assess the contributions of GSK-3β to both α-Syn and Tau phosphorylation. Behavioral studies revealed progressive age-dependent impairment of motor function, accompanied by loss of tyrosine hydroxylase-positive (TH+ DA-neurons) neurons and dopamine production in the oldest age group. Magnetic resonance imaging revealed deterioration of the substantia nigra in aged mice, a characteristic feature of PD patients. At the molecular level, kinase-active p-GSK-3β-Y216 was seen at all ages throughout the brain, yet elevated levels of p-α-Syn-S129 and p-Tau (S396/404) were found to increase with age exclusively in TH+ DA-neurons of the midbrain. p-GSK-3β-Y216 colocalized with p-Tau and p-α-Syn-S129. In vitro kinase assays showed that recombinant human GSK-3β directly phosphorylated α-Syn at a single site, Ser129, in addition to its known ability to phosphorylate Tau. Moreover, α-Syn and Tau together cooperated with one another to increase the magnitude or rate of phosphorylation of the other by GSK-3β. Together, these data establish a novel upstream role for GSK-3β as one of several kinases associated with PTMs of key proteins known to be causal in PD.

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“…69 A major cause of functional deficits after SCI is the secondary death of neurons and oligodendrocytes resulting from excitotoxic and inflammatory apoptosis. 2,6 In this regard, substantial evidence suggests that Wnt signaling might play a critical role in determining the balance between neuronal survival and death in a variety of neurodegenerative states, [70][71][72][73][74][75] brain ischemia, 64,76 and excitotoxicity. 18,77 For example, GSK-3b inhibition by lithium 78 or Wnt3a 79 (both of which activate Wnt/b-catenin signaling) have been shown to exert neuroprotective effects during SCI.…”

Section: Discussionmentioning

confidence: 99%

Wnts Are Expressed in the Spinal Cord of Adult Mice and Are Differentially Induced after Injury

González-Fernández

Fernández-Martos

Shields

et al. 2014

Journal of Neurotrauma

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The Wnt family of proteins plays key roles during central nervous system development and has been involved in several neuropathologies during adulthood, including spinal cord injury (SCI). However, Wnts expression knowledge is relatively limited during adult stages. Here, we sought to define the Wnt family expression pattern after SCI in adult mice by using quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC). Under physiological conditions, the messenger RNAs (mRNAs) of most Wnt ligands, inhibitors, receptors, and coreceptors are constitutively expressed in healthy adult mice. After dorsal hemisection, we found significant time-dependent variations, with a prominent upregulation of Wnt inhibitory factor 1 (Wif1). IHC against Frizzled (Fz) 1 and Fz4, as representatives of late and acute upregulated receptors, showed a differential expression in the uninjured spinal cord of Fz1 by neurons and oligodendrocytes and Fz4 by astrocytes. After injury, both receptors were maintained in the same type of cells. Finally, by using BATgal reporter mice, our results revealed active b-catenin signaling in neurons of the dorsal horn and cells of the central canal of uninjured spinal cords, besides a lack of additional SCI-induced activation.In conclusion, we demonstrate Wnt expression in the adult spinal cord of mice that is modulated by SCI, which differs from that previously described in rats. Further, Fz receptors are differentially expressed by neurons and glial cells, suggestive for cell-specific patterns and thus diverse physiological roles. Further studies will help toward in-depth characterization of the role of all Wnt factors and receptors described and eventually allow for the design of novel therapies.

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Reactive astrocytes and Wnt/β-catenin signaling link nigrostriatal injury to repair in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease

Cited by 171 publications

References 106 publications

Neuroprotective Effect of Progesterone in MPTP-Treated Male Mice

Neuroprotective Effect of Progesterone in MPTP-Treated Male Mice

GSK-3β dysregulation contributes to parkinson’s-like pathophysiology with associated region-specific phosphorylation and accumulation of tau and α-synuclein

Wnts Are Expressed in the Spinal Cord of Adult Mice and Are Differentially Induced after Injury

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