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Astrocytic JWA expression is essential to dopaminergic neuron survival in the pathogenesis of Parkinson's disease.

ABSTRACT: AIMS:To investigate the role of astrocytic JWA expression in dopaminergic (DA) neuron degeneration and in the pathogenesis of Parkinson's disease (PD). METHODS:Conditional astrocytic JWA null (JWA∆2/∆2/GFAP-Cre) mice and U251 glioma cells were used to evaluate the effects of JWA gene on DA neuron degeneration. The oxidative stress-driven molecular events were determined in both in vivo and in vitro models. RESULTS:Conditional astrocytic JWA knockout resulted in significant activation of astrocytes measured by increase in glial fibrillary acidic protein-positive cells (1.34×10(3)±74.5 vs. 8.44×10(3)±1.35×10(3), P<0.01) in mouse substantia nigra, accompanied by loss of DA neurons (1.03×10(4)±238 vs. 6.17×10(3)±392, P<0.001). Deficiency of JWA significantly aggravated reactive oxygen species (ROS) accumulation in substantia nigra compared with the wild-type mice. Increasing JWA expression in U251 glioma cells inhibited ROS with a concomitant increase in intracellular glutathione. Furthermore, suppression of IKKβ-nuclear factor (NF)-κB signaling pathway was shown to regulate JWA in a PD model. CONCLUSIONS:The JWA gene exerts neuroprotective roles against DA neuronal degeneration via modulating intracellular redox status and NF-κB signaling pathway and is a potential treatment target for PD.

SUBMITTER: Miao SH

PROVIDER: S-EPMC6493088 | biostudies-other | 2014 Aug

REPOSITORIES: biostudies-other

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Astrocytic JWA expression is essential to dopaminergic neuron survival in the pathogenesis of Parkinson's disease.

Miao Shu-Han SH Sun Hong-Bin HB Ye Yang Y Yang Jing-Jing JJ Shi Yao-Wei YW Lu Ming M Hu Gang G Zhou Jian-Wei JW

CNS neuroscience & therapeutics 20140317 8

<h4>Aims</h4>To investigate the role of astrocytic JWA expression in dopaminergic (DA) neuron degeneration and in the pathogenesis of Parkinson's disease (PD).<h4>Methods</h4>Conditional astrocytic JWA null (JWA∆2/∆2/GFAP-Cre) mice and U251 glioma cells were used to evaluate the effects of JWA gene on DA neuron degeneration. The oxidative stress-driven molecular events were determined in both in vivo and in vitro models.<h4>Results</h4>Conditional astrocytic JWA knockout resulted in significant ...[more]

PMID: 24628733

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Project description:In the brain, programmed cell death (PCD) serves to adjust the numbers of the different types of neurons during development, and its pathological reactivation in the adult leads to neurodegeneration. Dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A) is a pleiotropic kinase involved in neural proliferation and cell death, and its role during brain growth is evolutionarily conserved. Human DYRK1A lies in the Down syndrome critical region on chromosome 21, and heterozygous mutations in the gene cause microcephaly and neurological dysfunction. The mouse model for DYRK1A haploinsufficiency (the Dyrk1a(+/-) mouse) presents neuronal deficits in specific regions of the adult brain, including the substantia nigra (SN), although the mechanisms underlying these pathogenic effects remain unclear. Here we study the effect of DYRK1A copy number variation on dopaminergic cell homeostasis. We show that mesencephalic DA (mDA) neurons are generated in the embryo at normal rates in the Dyrk1a haploinsufficient model and in a model (the mBACtgDyrk1a mouse) that carries three copies of Dyrk1a. We also show that the number of mDA cells diminishes in postnatal Dyrk1a(+/-) mice and increases in mBACtgDyrk1a mice due to an abnormal activity of the mitochondrial caspase9 (Casp9)-dependent apoptotic pathway during the main wave of PCD that affects these neurons. In addition, we show that the cell death induced by 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP), a toxin that activates Casp9-dependent apoptosis in mDA neurons, is attenuated in adult mBACtgDyrk1a mice, leading to an increased survival of SN DA neurons 21 days after MPTP intoxication. Finally, we present data indicating that Dyrk1a phosphorylation of Casp9 at the Thr125 residue is the mechanism by which this kinase hinders both physiological and pathological PCD in mDA neurons. These data provide new insight into the mechanisms that control cell death in brain DA neurons and they show that deregulation of developmental apoptosis may contribute to the phenotype of patients with imbalanced DYRK1A gene dosage.

Dataset Information

Astrocytic JWA expression is essential to dopaminergic neuron survival in the pathogenesis of Parkinson's disease.

Publications

Astrocytic JWA expression is essential to dopaminergic neuron survival in the pathogenesis of Parkinson's disease.

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