Enhanced sensitivity of DJ-1-deficient dopaminergic neurons to energy metabolism impairment: Role of Na+/K+ ATPase

Pisani, Antonio; Martella, Giuseppina; Tscherter, Anne; Costa, Cinzia; Mercuri, Nicola Biagio; Bernardi, Giorgio; Shen, Jie; Calabresi, Paolo

doi:10.1016/j.nbd.2006.02.001

Cited by 49 publications

(24 citation statements)

References 35 publications

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“…Interestingly, Pisani et al (42), have demonstrated that DJ-1-deficient dopaminergic neurons show enhanced sensitivity to energy metabolism impairment when they assess the responses of dopaminergic cells to combined oxygen and glucose deprivation. This appears of particular interest because other authors reported that even an early stage of Parkinson's disease causes a subnormal response to hypoxia (43), and DJ-1, whose gene mutations lead to an inherited form of early-onset parkinsonism, is mainly involved in dopaminergic neuronal function in this pathology (11).…”

Section: Discussionmentioning

confidence: 99%

DJ-1/PARK7 is an important mediator of hypoxia-induced cellular responses

Vasseur

Afzal

Tardivel-Lacombe

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

195

157

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In cancer, DJ-1/PARK7 acts as an oncogene that drives Akt-mediated cell survival. Although amplification of DJ-1 has been described in several types of tumors, the mechanistic basis of DJ-1's oncogenic effect remains incompletely understood. A tumor's ability to adapt to hypoxia is absolutely critical for its survival and progression, and this adaptation is largely mediated by the transcription factor HIF1. The stabilization of HIF1 subunits during hypoxia is at least partly dependent on the PI3K/Akt/mTOR pathway. We hypothesized that DJ-1, a positive regulator of Akt when over-expressed, might be involved in regulating HIF1 transcriptional activity under hypoxic conditions. Our results show that loss of DJ-1 in human cell lines and transformed mouse fibroblasts decreases the transcription of a variety of HIF1-responsive genes during hypoxia. Moreover, DJ-1 expression is critical for the Akt and mTOR activities that sustain HIF1 stability. Surprisingly, DJ-1 also regulates the activity of the metabolic sensor AMPK, especially during hypoxia. Finally, DJ-1 appears to protect cells against hypoxia-induced cell death and is required for their adaptation to severe hypoxic stress. Our work positions DJ-1 as an upstream activator of HIF1 function in cancer cells and establishes that DJ-1's oncogenic activity stems from its ability to increase a cell's resistance to hypoxic stress through DJ-1's regulatory effects on mTOR and AMPK. The discovery of these functions of DJ-1 strengthens the case for the development of therapeutics that target DJ-1 activity in cancer cells.mTOR ͉ AMPK ͉ apoptosis

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Section: Discussionmentioning

confidence: 99%

DJ-1/PARK7 is an important mediator of hypoxia-induced cellular responses

Vasseur

Afzal

Tardivel-Lacombe

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

195

157

View full text Add to dashboard Cite

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“…To this end, several themes regarding DJ-1 have now emerged that link this protein to neurodegeneration, PD, and oxidative stress. These themes include, but are not limited to the following: (i) DJ-1 protects neurons against oxidative stress (4,9,11,(41)(42)(43)(44); (ii) Loss of DJ-1 on its own does not lead to dopamine neuron death, at least in mice, but DJ-1-deficient animals are sensitized to environmental stress and exhibit impaired dopamine signaling (45)(46)(47)(48); and (iii) DJ-1 modulates signaling pathways critical to cell survival such as PTEN and AKT, at least in select nonneuronal contexts (31).…”

Section: Dj-1 Modulates Akt Translocation To Membranous Fractionsmentioning

confidence: 99%

DJ-1 protects the nigrostriatal axis from the neurotoxin MPTP by modulation of the AKT pathway

Aleyasin

Rousseaux

Marcogliese

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

155

118

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Loss-of-function DJ-1 (PARK7) mutations have been linked with a familial form of early onset Parkinson disease. Numerous studies have supported the role of DJ-1 in neuronal survival and function. Our initial studies using DJ-1-deficient neurons indicated that DJ-1 specifically protects the neurons against the damage induced by oxidative injury in multiple neuronal types and degenerative experimental paradigms, both in vitro and in vivo. However, the manner by which oxidative stress-induced death is ameliorated by DJ-1 is not completely clear. We now present data that show the involvement of DJ-1 in modulation of AKT, a major neuronal prosurvival pathway induced upon oxidative stress. We provide evidence that DJ-1 promotes AKT phosphorylation in response to oxidative stress induced by H 2 O 2 in vitro and in vivo following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment. Moreover, we show that DJ-1 is necessary for normal AKT-mediated protective effects, which can be bypassed by expression of a constitutively active form of AKT. Taken together, these data suggest that DJ-1 is crucial for full activation of AKT upon oxidative injury, which serves as one explanation for the protective effects of DJ-1.neurodegeneration | Parkinson disease | reactive oxygen species

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“…Therefore, the lack of DJ-l would produce impairment in the activity ofthe Na+/K+ pump which certainly favors an irreversible depolarization of the dopamine cells caused by rotenone (36). In addition, rotenone has been also reported to cause a PKAmediated reduction of delayed rectifier potassium channels in rat midbrain cultured neurons (37).…”

Section: Neurotoxicity Induced By Rotenone On Dopaminergic Cellsmentioning

confidence: 99%

Paraquat-and Rotenone-Induced Models of Parkinson's Disease

Nisticò

Mehdawy

Piccirilli

et al. 2011

Int J Immunopathol Pharmacol

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Parkinson's disease (PD) is a neurodegenerative disorder mainly characterized by a loss of dopaminergic (DA) neurons in the substantia nigra pars compacta. In recent years, several new genes and environmental factors have been implicated in PD, and their impact on DA neuronal cell death is slowly emerging. However, PD etiology remains unknown, whereas its pathogenesis begins to be clarified as a multifactorial cascade of deleterious factors. Recent epidemiological studies have linked exposure to environmental agents, including pesticides, with an increased risk of developing the disease. As a result, over the last two decades the ‘environmental hypothesis’ of PD has gained considerable interest. This speculates that agricultural chemicals in the environment, by producing selective dopaminergic cell death, can contribute to the development of the disease. However, a causal role for pesticides in the etiology of PD has yet to be definitively established. Importantly, most insights into PD pathogenesis came from investigations performed in experimental models of PD, especially those produced by neurotoxins. This review presents data obtained in our laboratories along with current views on the neurotoxic actions induced by the two most popular parkinsonian pesticide neurotoxins, namely paraquat and rotenone. Although confined to these two chemicals, mechanistic studies underlying dopaminergic cell death are of the utmost importance to identify new drug targets for the treatment of PD.

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Enhanced sensitivity of DJ-1-deficient dopaminergic neurons to energy metabolism impairment: Role of Na+/K+ ATPase

Cited by 49 publications

References 35 publications

DJ-1/PARK7 is an important mediator of hypoxia-induced cellular responses

DJ-1/PARK7 is an important mediator of hypoxia-induced cellular responses

DJ-1 protects the nigrostriatal axis from the neurotoxin MPTP by modulation of the AKT pathway

Paraquat-and Rotenone-Induced Models of Parkinson's Disease

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