Parkinson's disease (PD) is a neurological disorder that involves the loss of dopaminergic neuron... more Parkinson's disease (PD) is a neurological disorder that involves the loss of dopaminergic neurons in the substantia nigra. Though PD is multifactorial, several reports show an increased incidence of PD with coexposure to pesticides such as Maneb and paraquat (MP). In pesticide-related PD, mitochondrial dysfunction and αsynuclein oligomers have been strongly implicated, but the link between the two is not yet understood. Similarly, the biological effects of α-synuclein or its radical chemistry in PD is largely unknown. Mitochondrial dysfunction during PD pathogenesis leads to release of cytochrome c in the cytosol. In the cytosol, cytochrome c has one of two fates: It either binds to apaf1 and initiates apoptosis or acts as a peroxidase. We hypothesized that as a peroxidase, cytochrome c leaked from mitochondria can form radicals on α-synuclein and initiate its oligomerization. Experiments with MP co-exposed mice showed cytochrome c release in cytosol and its co-localization with α-synuclein. Immunospin trapping experiments of samples from an in vitro reaction mixture consisting of cytochrome c, α-synuclein, and hydrogen peroxide indicated that cytochrome c catalyzes α-synuclein radical formation and oligomerization. Experiments with MP co-exposed α-synuclein knockout mice, in which cytochrome c-α synuclein colocalization and interaction can not occur, mice showed diminished protein radical formation, minimal changes in overall gene expression and diminished neuronal death compared to wild-type MP co-exposed mice. Altogether, these results show that peroxidase activity of cytochrome c contributes to α-synuclein radical formation and oligomerization, and that α-synuclein, through its co-localization with cytochrome c or on its own, affects several biological pathways which contribute to increased neuronal death in an MP-induced model of PD.
Loss of dopaminergic nigrostriatal neurons in the substantia nigra leads to Parkinson’s disease (... more Loss of dopaminergic nigrostriatal neurons in the substantia nigra leads to Parkinson’s disease (PD). Adenosine A2A receptors (A2ARs) have been anticipated as novel therapeutic target for PD. A2ARs potentiate locomotor behavior and are predominantly expressed in striatum. Naphtha [1, 2-d] thiazol-2-amine (NATA), a tricyclic thiazole have been studied as new anti-Parkinsonian compound. AutoDock analysis and pharmacophore study of NATA with known A2AR antagonists explicit its efficacy as a possible adenosine receptor antagonist. In vivo pharmacology of NATA showed reduction of haloperidol (HAL)-induced motor impairments in Swiss albino male mice. Relatively elevated levels of dopamine inNATA pre-treated mice are suggestive of its possible role as neuromodulator in PD.
Parkinson's disease (PD) is a neurological disorder that involves the loss of dopaminergic neuron... more Parkinson's disease (PD) is a neurological disorder that involves the loss of dopaminergic neurons in the substantia nigra. Though PD is multifactorial, several reports show an increased incidence of PD with coexposure to pesticides such as Maneb and paraquat (MP). In pesticide-related PD, mitochondrial dysfunction and αsynuclein oligomers have been strongly implicated, but the link between the two is not yet understood. Similarly, the biological effects of α-synuclein or its radical chemistry in PD is largely unknown. Mitochondrial dysfunction during PD pathogenesis leads to release of cytochrome c in the cytosol. In the cytosol, cytochrome c has one of two fates: It either binds to apaf1 and initiates apoptosis or acts as a peroxidase. We hypothesized that as a peroxidase, cytochrome c leaked from mitochondria can form radicals on α-synuclein and initiate its oligomerization. Experiments with MP co-exposed mice showed cytochrome c release in cytosol and its co-localization with α-synuclein. Immunospin trapping experiments of samples from an in vitro reaction mixture consisting of cytochrome c, α-synuclein, and hydrogen peroxide indicated that cytochrome c catalyzes α-synuclein radical formation and oligomerization. Experiments with MP co-exposed α-synuclein knockout mice, in which cytochrome c-α synuclein colocalization and interaction can not occur, mice showed diminished protein radical formation, minimal changes in overall gene expression and diminished neuronal death compared to wild-type MP co-exposed mice. Altogether, these results show that peroxidase activity of cytochrome c contributes to α-synuclein radical formation and oligomerization, and that α-synuclein, through its co-localization with cytochrome c or on its own, affects several biological pathways which contribute to increased neuronal death in an MP-induced model of PD.
Loss of dopaminergic nigrostriatal neurons in the substantia nigra leads to Parkinson’s disease (... more Loss of dopaminergic nigrostriatal neurons in the substantia nigra leads to Parkinson’s disease (PD). Adenosine A2A receptors (A2ARs) have been anticipated as novel therapeutic target for PD. A2ARs potentiate locomotor behavior and are predominantly expressed in striatum. Naphtha [1, 2-d] thiazol-2-amine (NATA), a tricyclic thiazole have been studied as new anti-Parkinsonian compound. AutoDock analysis and pharmacophore study of NATA with known A2AR antagonists explicit its efficacy as a possible adenosine receptor antagonist. In vivo pharmacology of NATA showed reduction of haloperidol (HAL)-induced motor impairments in Swiss albino male mice. Relatively elevated levels of dopamine inNATA pre-treated mice are suggestive of its possible role as neuromodulator in PD.
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Papers by Rita Kumari
Adenosine A2A receptors (A2ARs) have been anticipated as novel therapeutic target for PD. A2ARs potentiate
locomotor behavior and are predominantly expressed in striatum. Naphtha [1, 2-d] thiazol-2-amine
(NATA), a tricyclic thiazole have been studied as new anti-Parkinsonian compound. AutoDock analysis
and pharmacophore study of NATA with known A2AR antagonists explicit its efficacy as a possible adenosine
receptor antagonist. In vivo pharmacology of NATA showed reduction of haloperidol (HAL)-induced
motor impairments in Swiss albino male mice. Relatively elevated levels of dopamine inNATA pre-treated
mice are suggestive of its possible role as neuromodulator in PD.
Adenosine A2A receptors (A2ARs) have been anticipated as novel therapeutic target for PD. A2ARs potentiate
locomotor behavior and are predominantly expressed in striatum. Naphtha [1, 2-d] thiazol-2-amine
(NATA), a tricyclic thiazole have been studied as new anti-Parkinsonian compound. AutoDock analysis
and pharmacophore study of NATA with known A2AR antagonists explicit its efficacy as a possible adenosine
receptor antagonist. In vivo pharmacology of NATA showed reduction of haloperidol (HAL)-induced
motor impairments in Swiss albino male mice. Relatively elevated levels of dopamine inNATA pre-treated
mice are suggestive of its possible role as neuromodulator in PD.