A Specific Survival Response in Dopamine Neurons at Most Risk in Parkinson's Disease

Murase, Sachiko; McKay, Ronald D.G.

doi:10.1523/jneurosci.2745-06.2006

Cited by 68 publications

(79 citation statements)

References 80 publications

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“…FoxA2 is a member of the foxo group of forkhead genes that are central mediators in cell survival. We have defined an FGF receptor, FGF-R1, expressed in the adult dopamine neurons at most risk in PD (van der Walt et al 2004;Murase and McKay 2006). These discoveries begin to define key cell-autonomous components of survival signaling that respond to the state of surrounding stem cells and astrocytes.…”

Section: Discussionmentioning

confidence: 99%

Signaling Pathways Controlling Neural Stem Cells Slow Progressive Brain Disease

Androutsellis-Theotokis¹,

Rueger²,

Mkhikian³

et al. 2008

Cold Spring Harbor Symposia on Quantitative Biology

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The identification and characterization of multipotent neural precursors open the possibility of transplant therapies, but this approach is complicated by the widespread pathology of many degenerative diseases. Activation of endogenous precursors that support regenerative mechanisms is a possible alternative. We have previously shown that Notch ligands promote stem cell survival in vitro. Here, we show that there is an intimate interaction between insulin and Notch receptor signaling. Notch ligands also expand stem cell numbers in vivo with correlated benefits in brain ischemia. We now show that insulin promotes recovery of injured dopamine neurons in the adult brain. This response suggests that activating survival mechanisms in neural stem cells will promote recovery from progressive degenerative disease.

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Section: Discussionmentioning

confidence: 99%

Signaling Pathways Controlling Neural Stem Cells Slow Progressive Brain Disease

Androutsellis-Theotokis¹,

Rueger²,

Mkhikian³

et al. 2008

Cold Spring Harbor Symposia on Quantitative Biology

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“…H 2 O 2 , in turn, can be reduced via the Fenton reaction in the presence of ferrous iron (Fe 2+ ), to produce the highly reactive and toxic hydroxyl radical ( • OH) (Hermida-Ameijeiras et al, 2004). Indeed, VMAT inhibition induces formation of reactive oxygen species and results in degeneration of mature DA neurons in culture, whereas inhibition of DAT does not produce these same toxic effects (Murase and McKay, 2006). In fact, a recent study by Caudle et al (2007) that used mice that express extremely low levels of VMAT demonstrated that these mice are under oxidative stress that eventually leads to degeneration of the nigrostriatal DA system.…”

Section: Discussionmentioning

confidence: 99%

Polychlorinated biphenyl-induced oxidative stress in organotypic co-cultures: Experimental dopamine depletion prevents reductions in GABA

Lyng

Seegal

2008

NeuroToxicology

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Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants that have been demonstrated to be toxic to the dopamine (DA) systems of the central nervous system. One proposed mechanism for PCB-induced DA neurotoxicity is inhibition of the vesicular monoamine transporter (VMAT); such inhibition results in increased levels of unsequestered DA and DA metabolism leading to oxidative stress. We have used an organotypic co-culture system of developing rat striatum and ventral mesencephalon (VM) to determine whether alterations in the vesicular storage of DA, resulting from PCB exposure and consequent induction of oxidative stress, leads to GABA and DA neuronal dysfunction. 24 hr exposure to an environmentally relevant mixture of PCBs reduced tissue DA and GABA concentrations, increased medium levels of DA and measures of oxidative stress in both the striatum and VM. Alterations in neurochemistry and increases in measures of oxidative stress were blocked in the presence of n-acetylcysteine (NAC). Although NAC treatment did not alter PCB-induced changes in DA neurochemistry, it did protect against reductions in GABA concentration. To determine whether alterations in the vesicular storage of DA were responsible for PCB-induced oxidative stress and consequent reductions in GABA levels, we depleted DA from the co-cultures using α-methyl-p-tyrosine (AMPT). AMPT reduced striatal and VM DA levels by 90% and 70%, respectively. PCB exposure, following DA depletion, neither increased levels of oxidative stress nor resulted in GABA depletion. These results suggest that PCB-induced alterations in the vesicular storage of DA, resulting in increased levels of unsequestered DA, leads to increased oxidative stress, depletion of tissue glutathione, and consequent reductions in tissue GABA concentrations.

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“…FGF20 selectively activates tyrosine hydroxylase and stimulates dopamine release in vitro from calbindin-negative neurons, which are progressively and preferentially lost in PD (Murase & McKay, 2006). Dopamine is catalyzed by MAOB in the oxidative deamination process to form H 2 O 2 and toxic aldehyde metabolites, which accelerate the degeneration of dopaminergic neurons in the substantia nigra (Nagatsu & Sawada, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…The FGF20 gene lies on chromosome 8p21.3-22 and has been found to be involved in survival of dopaminergic cells (Murase & McKay, 2006). Several genetic studies implicate FGF20 in PD risk.…”

Section: Introductionmentioning

confidence: 99%

Gene‐Gene Interaction Between FGF20 and MAOB in Parkinson Disease

Gao

Scott

Wang

et al. 2008

Annals of Human Genetics

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SummaryThe fibroblast growth factor 20 (FGF20) and monoamine oxidase B (MAOB) genes are associated with Parkinson Disease (PD) risk and both are in the dopamine bio-pathway. Therefore, we investigated the joint effect between polymorphisms in the FGF20 and MAOB genes for evidence of interaction contributing to PD risk. Fourteen polymorphisms (eight for FGF20, six for MAOB) were genotyped in 736 families and analyzed using conditional logistic regression (CLR). Significant two-locus interactions were found in females between the polymorphisms rs1721100 of FGF20 and rs1799836 of MAOB, and between the polymorphisms rs1721082 of FGF20 and rs1799836 of MAOB. The risk alleles for each SNP identified from CLR, rs1721100 C, rs1721082 T and rs1799836 A, are consistent with previous reports. Using indicator variables for the SNP genotypes, rs1721100 GC with rs1799836 AA showed significant interaction (P = 0.021), compared with the reference group rs1721100 GG with rs1799836 GG. Using an allele-dose model for the risk alleles, rs1721100 and rs1799836 showed significant interaction (P = 0.019). We found similar interaction results between rs1721082 and rs1799836. In conclusion, variants in FGF20 and MAOB show evidence of statistical interactions, which emphasizes the importance of considering them jointly in genetic analysis of PD and illustrates potential patterns of biological interaction contributing to PD risk.

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A Specific Survival Response in Dopamine Neurons at Most Risk in Parkinson's Disease

Cited by 68 publications

References 80 publications

Signaling Pathways Controlling Neural Stem Cells Slow Progressive Brain Disease

Signaling Pathways Controlling Neural Stem Cells Slow Progressive Brain Disease

Polychlorinated biphenyl-induced oxidative stress in organotypic co-cultures: Experimental dopamine depletion prevents reductions in GABA

Gene‐Gene Interaction Between FGF20 and MAOB in Parkinson Disease

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