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000138219 0247_ $$2doi$$a10.1016/j.nbd.2015.05.015
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000138219 0247_ $$2ISSN$$a0969-9961
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000138219 037__ $$aDZNE-2020-04541
000138219 041__ $$aEnglish
000138219 082__ $$a570
000138219 1001_ $$aZhang, Jingzhong$$b0
000138219 245__ $$aA WNT1-regulated developmental gene cascade prevents dopaminergic neurodegeneration in adult En1(+/-) mice.
000138219 260__ $$aOrlando, Fla.$$bAcademic Press$$c2015
000138219 264_1 $$2Crossref$$3print$$bElsevier BV$$c2015-10-01
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000138219 520__ $$aThe protracted and age-dependent degeneration of dopamine (DA)-producing neurons of the Substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) in the mammalian midbrain is a hallmark of human Parkinson's Disease (PD) and of certain genetic mouse models of PD, such as mice heterozygous for the homeodomain transcription factor Engrailed 1 (En1(+/-) mice). Neurotoxin-based animal models of PD, in contrast, are characterized by the fast and partly reversible degeneration of the SNc and VTA DA neurons. The secreted protein WNT1 was previously shown to be strongly induced in the neurotoxin-injured adult ventral midbrain (VM), and to protect the SNc and VTA DA neurons from cell death in this context. We demonstrate here that the sustained and ectopic expression of Wnt1 in the SNc and VTA DA neurons of En1(+/Wnt1) mice also protected these genetically affected En1 heterozygote (En1(+/-)) neurons from their premature degeneration in the adult mouse VM. We identified a developmental gene cascade that is up-regulated in the adult En1(+/Wnt1) VM, including the direct WNT1/β-catenin signaling targets Lef1, Lmx1a, Fgf20 and Dkk3, as well as the indirect targets Pitx3 (activated by LMX1A) and Bdnf (activated by PITX3). We also show that the secreted neurotrophin BDNF and the secreted WNT modulator DKK3, but not the secreted growth factor FGF20, increased the survival of En1 mutant dopaminergic neurons in vitro. The WNT1-mediated signaling pathway and its downstream targets BDNF and DKK3 might thus provide a useful means to treat certain genetic and environmental (neurotoxic) forms of human PD.
000138219 536__ $$0G:(DE-HGF)POF3-342$$a342 - Disease Mechanisms and Model Systems (POF3-342)$$cPOF3-342$$fPOF III$$x0
000138219 542__ $$2Crossref$$i2015-10-01$$uhttps://www.elsevier.com/tdm/userlicense/1.0/
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000138219 650_7 $$2NLM Chemicals$$aBrain-Derived Neurotrophic Factor
000138219 650_7 $$2NLM Chemicals$$aDkk3 protein, mouse
000138219 650_7 $$2NLM Chemicals$$aEn1 protein, mouse
000138219 650_7 $$2NLM Chemicals$$aHomeodomain Proteins
000138219 650_7 $$2NLM Chemicals$$aIntercellular Signaling Peptides and Proteins
000138219 650_7 $$2NLM Chemicals$$aWnt1 Protein
000138219 650_2 $$2MeSH$$aAdaptor Proteins, Signal Transducing
000138219 650_2 $$2MeSH$$aAnimals
000138219 650_2 $$2MeSH$$aBrain-Derived Neurotrophic Factor: genetics
000138219 650_2 $$2MeSH$$aBrain-Derived Neurotrophic Factor: metabolism
000138219 650_2 $$2MeSH$$aCell Differentiation: genetics
000138219 650_2 $$2MeSH$$aDopaminergic Neurons: metabolism
000138219 650_2 $$2MeSH$$aDopaminergic Neurons: pathology
000138219 650_2 $$2MeSH$$aGene Expression Regulation, Developmental
000138219 650_2 $$2MeSH$$aHomeodomain Proteins: genetics
000138219 650_2 $$2MeSH$$aIntercellular Signaling Peptides and Proteins: genetics
000138219 650_2 $$2MeSH$$aIntercellular Signaling Peptides and Proteins: metabolism
000138219 650_2 $$2MeSH$$aMice
000138219 650_2 $$2MeSH$$aMice, Transgenic
000138219 650_2 $$2MeSH$$aNerve Degeneration: genetics
000138219 650_2 $$2MeSH$$aNerve Degeneration: metabolism
000138219 650_2 $$2MeSH$$aNerve Degeneration: pathology
000138219 650_2 $$2MeSH$$aParkinson Disease: metabolism
000138219 650_2 $$2MeSH$$aParkinson Disease: pathology
000138219 650_2 $$2MeSH$$aSignal Transduction: genetics
000138219 650_2 $$2MeSH$$aSubstantia Nigra: metabolism
000138219 650_2 $$2MeSH$$aSubstantia Nigra: pathology
000138219 650_2 $$2MeSH$$aUp-Regulation
000138219 650_2 $$2MeSH$$aVentral Tegmental Area: metabolism
000138219 650_2 $$2MeSH$$aVentral Tegmental Area: pathology
000138219 650_2 $$2MeSH$$aWnt1 Protein: metabolism
000138219 7001_ $$aGötz, Sebastian$$b1
000138219 7001_ $$0P:(DE-2719)9000331$$aVogt-Weisenhorn, Daniela$$b2$$udzne
000138219 7001_ $$aSimeone, Antonio$$b3
000138219 7001_ $$0P:(DE-2719)2000028$$aWurst, Wolfgang$$b4$$eCorresponding author$$udzne
000138219 7001_ $$0P:(DE-HGF)0$$aPrakash, Nilima$$b5
000138219 77318 $$2Crossref$$3journal-article$$a10.1016/j.nbd.2015.05.015$$b : Elsevier BV, 2015-10-01$$p32-45$$tNeurobiology of Disease$$v82$$x0969-9961$$y2015
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