Changes in Neuronal Dopamine Homeostasis following 1-Methyl-4-phenylpyridinium (MPP+) Exposure

Choi, Se Joon; Panhelainen, Anne; Schmitz, Yvonne; Larsen, Kristin E.; Kanter, Ellen; Wu, Min; Sulzer, David; Mosharov, Eugene V.

doi:10.1074/jbc.m114.631556

Cited by 50 publications

(33 citation statements)

References 84 publications

(75 reference statements)

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“…; Choi et al . ). After treatment, cells were fixed with 4% Paraformaldehyde (PFA) for 30 min, washed three times with phosphate‐buffered saline and stained with Hoechst 33258 (0.5 ng/mL) (Cat.…”

Section: Methodsmentioning

confidence: 97%

“…#D048) for 48 h as a described previously (Qu et al 2007(Qu et al , 2015. MPP + has been used to induce an in vitro cell model of PD (Burke 2007) where MPP + , as an inhibitor of complex I of the mitochondrial electron transport chain, induces oxidative stress and energy deficits (Burke 2007;Keane et al 2011;Choi et al 2015). After treatment, cells were fixed with 4% Paraformaldehyde (PFA) for 30 min, washed three times with phosphate-buffered saline and stained with Hoechst 33258 (0.5 ng/mL) (Cat.…”

Section: Recombinant Protein Preparation and In Vitro Kinase Assaymentioning

confidence: 99%

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Pink1 regulates FKBP5 interaction with AKT/PHLPP and protects neurons from neurotoxin stress induced by MPP⁺

Boonying

Joselin

Huang

et al. 2019

Journal of Neurochemistry

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Loss of function mutations in the PTEN‐induced putative kinase 1 (Pink1) gene have been linked with an autosomal recessive familial form of early onset Parkinson's disease (PD). However, the underlying mechanism(s) responsible for degeneration remains elusive. Presently, using co‐immunoprecipitation in HEK (Human embryonic kidney) 293 cells, we show that Pink1 endogenously interacts with FK506‐binding protein 51 (FKBP51 or FKBP5), FKBP5 and directly phosphorylates FKBP5 at Serine in an in vitro kinase assay. Both FKBP5 and Pink1 have been previously associated with protein kinase B (AKT) regulation. We provide evidence using primary cortical cultured neurons from Pink1‐deficient mice that Pink1 increases AKT phosphorylation at Serine 473 (Ser473) challenged by 1‐methyl‐4‐phenylpyridinium (MPP+) and that over‐expression of FKBP5 using an adeno‐associated virus delivery system negatively regulates AKT phosphorylation at Ser473 in murine‐cultured cortical neurons. Interestingly, FKBP5 over‐expression promotes death in response to MPP+ in the absence of Pink1. Conversely, shRNA‐mediated knockdown of FKBP5 in cultured cortical neurons is protective and this effect is reversed with inhibition of AKT signaling. In addition, shRNA down‐regulation of PH domain leucine‐rich repeat protein phosphatase (PHLPP) in Pink1 WT neurons increases neuronal survival, while down‐regulation of PHLPP in Pink1 KO rescues neuronal death in response to MPP+. Finally, using co‐immunoprecipitation, we show that FKBP5 interacts with the kinase AKT and phosphatase PHLPP. This interaction is increased in the absence of Pink1, both in Mouse Embryonic Fibroblasts (MEF) and in mouse brain tissue. Expression of kinase dead Pink1 (K219M) enhances FKBP5 interaction with both AKT and PHLPP. Overall, our results suggest a testable model by which Pink1 could regulate AKT through phosphorylation of FKBP5 and interaction of AKT with PHLPP. Our results suggest a potential mechanism by which PINK1‐FKBP5 pathway contributes to neuronal death in PD. Open Science Badges This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.

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Section: Methodsmentioning

confidence: 97%

Section: Recombinant Protein Preparation and In Vitro Kinase Assaymentioning

confidence: 99%

Pink1 regulates FKBP5 interaction with AKT/PHLPP and protects neurons from neurotoxin stress induced by MPP⁺

Boonying

Joselin

Huang

et al. 2019

Journal of Neurochemistry

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“…tegmental area (VTA; A10), and a third smaller cluster, found in the retrorubral area (A8; Bjorklund, & Dunnett, 2007;Fu et al, 2012;Nestler, Hyman, & Malenka, 2009;Zaborszky, & Vadasz, 2001). Despite resembling each other in many respects, dopamine neurons of the SNc and VTA mediate distinct neurological functions and exhibit dissimilar responses to toxins and addictive agents (Choi et al, 2015;Macdonald & Monchi, 2011;Teo, van Wyk, Lin, & Lipski, 2004). Since the discovery of dopamine as a neurotransmitter (Carlsson, Falck, & Hillarp, 1962) and the observation that it is depleted significantly in the SNc of patients with Parkinson's disease (Benazzouz et al, 2014;Hornykiewicz, & Kish, 1987;Tremblay et al, 2015), the regionally selective vulnerability of dopamine neurons has been the focus of a large number of studies (Bernheimer et al, 1973;Braak & Braak, 1986;Braak et al, 2003;Burns et al, 1983;Damier, Hirsch, Agid, & Graybiel, 1999;Double, Reyes, Werry, & Halliday, 2010;Fearnley & Lees, 1991;German, Manaye, Sonsalla, & Brooks, 1992;Gibb & Lees, 1991;Greenfield & Bosanquet, 1953;Halliday & Tork, 1986;Hirsch, Graybiel, & Agid, 1989;Poulin et al, 2014).…”

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confidence: 99%

HIV‐1 Tat regulation of dopamine transmission and microglial reactivity is brain region specific

Miller

Shaerzadeh

Phan

et al. 2018

Glia

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The transactivator of transcription protein, HIV-1 Tat, is linked to neuroAIDS, where degeneration of dopamine neurons occurs. Using a mouse model expressing GFAP-driven Tat protein under doxycycline (Dox) regulation, we investigated microglial-neuronal interactions in the rostral substantia nigra pars compacta (SNc). Immunohistochemistry for microglia and tyrosine hydroxylase (TH) showed that the ratio of microglia to dopamine neurons is smaller in the SNc than in the ventral tegmental area (VTA) and that this difference is maintained following 7-day Dox exposure in wild type animals. Administration of Dox to wild types had no effect on microglial densities. In addressing the sensitivity of neurons to potentially adverse effects of HIV-1 Tat, we found that HIV-1 Tat exposure in vivo selectively decreased TH immunoreactivity in the SNc but not in the VTA, while levels of TH mRNA in the SNc remained unchanged. HIV-1 Tat induction in vivo did not alter the total number of neurons in these brain regions. Application of Tat (5 ng) into dopamine neurons with whole-cell patch pipette decreased spontaneous firing activity. Tat induction also produced a decline in microglial cell numbers, but no microglial activation. Thus, disappearance of dopaminergic phenotype is due to a loss of TH immunoreactivity rather than to neuronal death, which would have triggered microglial activation. We conclude that adverse effects of HIV-1 Tat produce a hypodopamine state by decreasing TH immunoreactivity and firing activity of dopamine neurons. Reduced microglial numbers after Tat exposure in vivo suggest impaired microglial functions and altered bidirectional interactions between dopamine neurons and microglia.

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“…DA then undergoes robust efflux from neurons into the extracellular space mediated by DA uptake transporters (DAT) [33, 37, 51]. Choi et al [12] reported abnormalities in the storage, DAT-mediated transport, and catabolic breakdown of DA in dopaminergic neurons treated with MPP + and suggested that accumulation of cytosolic DA accounts for 30% of MPP + -mediated toxicity. These findings support a role for DA in the vulnerability of dopaminergic neurons to MPP + and other oxidative insults as well.…”

Section: Discussionmentioning

confidence: 99%

Direct intranigral injection of dopaminochrome causes degeneration of dopamine neurons

Touchette

Breckenridge

Wilken

et al. 2016

Neuroscience Letters

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Parkinson's disease (PD) is characterized by progressive neurodegeneration of nigrastriatal dopaminergic neurons leading to clinical motor dysfunctions. Many animal models of PD have been developed using exogenous neurotoxins and pesticides. Evidence strongly indicates that the dopaminergic neurons of the substantia nigra pars compacta (SNpc) are highly susceptible to neurodegeneration due to a number of factors including oxidative stress and mitochondrial dysfunction. Oxidation of DA to a potential endogenous neurotoxin, dopaminochrome (DAC), may be a potential contributor to the vulnerability of the nigrostriatal tract to oxidative insult. In this study, we show that DAC causes slow and progressive degeneration of dopaminergic neurons in contrast to 1-methyl-4-phenylpyridinium (MPP+), which induces rapid lesions of the region. The DAC model may be more reflective of early stresses that initiate the progressive neurodegenerative process of PD, and may prove a useful model for future neurodegenerative studies.

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Changes in Neuronal Dopamine Homeostasis following 1-Methyl-4-phenylpyridinium (MPP+) Exposure

Cited by 50 publications

References 84 publications

Pink1 regulates FKBP5 interaction with AKT/PHLPP and protects neurons from neurotoxin stress induced by MPP⁺

Pink1 regulates FKBP5 interaction with AKT/PHLPP and protects neurons from neurotoxin stress induced by MPP⁺

HIV‐1 Tat regulation of dopamine transmission and microglial reactivity is brain region specific

Direct intranigral injection of dopaminochrome causes degeneration of dopamine neurons

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Changes in Neuronal Dopamine Homeostasis following 1-Methyl-4-phenylpyridinium (MPP+) Exposure

Cited by 50 publications

References 84 publications

Pink1 regulates FKBP5 interaction with AKT/PHLPP and protects neurons from neurotoxin stress induced by MPP+

Pink1 regulates FKBP5 interaction with AKT/PHLPP and protects neurons from neurotoxin stress induced by MPP+

HIV‐1 Tat regulation of dopamine transmission and microglial reactivity is brain region specific

Direct intranigral injection of dopaminochrome causes degeneration of dopamine neurons

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Product

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Pink1 regulates FKBP5 interaction with AKT/PHLPP and protects neurons from neurotoxin stress induced by MPP⁺

Pink1 regulates FKBP5 interaction with AKT/PHLPP and protects neurons from neurotoxin stress induced by MPP⁺