Redox Modulation of Mitochondrial Proteins in the Neurotoxicant Models of Parkinson's Disease.

Significance: Mitochondrial proteins regulate the oxidative phosphorylation, cellular metabolism, and free radical generation. Redox modulation alters the mitochondrial proteins and instigates the damage to dopaminergic neurons. Toxicants contribute to Parkinson's disease (PD) pathogenesis in conjunction with aging and genetic factors. While oxidative modulation of a number of mitochondrial proteins is linked to xenobiotic exposure, little is known about its role in the toxicant-induced PD. Understanding the role of redox modulation of mitochondrial proteins in complex cellular events leading to neurodegeneration is highly relevant. Recent Advances: Many toxicants are shown to inhibit complex I or III and elicit free radical production that alters the redox status of mitochondrial proteins. Implication of redox modulation of the mitochondrial proteins makes them a target to comprehend the underlying mechanism of toxicant-induced PD. Critical Issues: Owing to multifactorial etiology, exploration of onset and progression and treatment outcomes needs a comprehensive approach. The article explains about a few mitochondrial proteins that undergo redox changes along with the promising strategies, which help to alleviate the toxicant-induced redox imbalance leading to neurodegeneration. Future Directions: Although mitochondrial proteins are linked to PD, their role in toxicant-induced parkinsonism is not yet completely known. Preservation of antioxidant defense machinery could alleviate the redox modulation of mitochondrial proteins. Targeted antioxidant delivery, use of metal chelators, and activation of nuclear factor erythroid 2-related factor 2, and combinational therapy that encounters multiple free radicals, could ameliorate the redox modulation of mitochondrial proteins and thereby PD progression. Antioxid. Redox Signal. 38, 824-852.

Resveratrol Regulates Nrf2-Mediated Expression of Antioxidant and Xenobiotic Metabolizing Enzymes in Pesticides-Induced Parkinsonism.

BACKGROUND: Combined maneb (MB) and paraquat (PQ), two widely used pesticides, increases oxidative stress leading to Parkinsonism. Xenobiotic metabolizing enzymes, cytochrome P450 (CYP) 2D6 and its mouse ortholog Cyp2d22 protect against Parkinsonism. Resveratrol, an antioxidant, restores antioxidant defense system through the activation of nuclear factor erythroid 2- related factor 2 (Nrf2). However, a crosstalk between Cyp2d22/CYP2D6-mediated protection and resveratrol-induced Nrf2 activation leading to neuroprotection is not yet elucidated. OBJECTIVE: The study aimed to decipher the effect of resveratrol on Nrf2 activation and expression of its downstream mediators, nicotinamide adenine dinucleotide phosphate quinone oxidoreductase 1 (NQO1) and thioredoxin 1 (Trx1) along with Cyp2d22/CYP2D6 activity in combined MB and PQ mouse model of Parkinsonism and differentiated neuroblastoma cells. RESULTS: MB and PQ reduced the dopamine content (mouse) and Cyp2d22/CYP2D6 activity (mouse/neuroblastoma cells) and increased the nuclear translocation of Nrf2 and expression of NQO1 and Trx1 (both). Resveratrol ameliorated pesticides-induced changes in dopamine content and Cyp2d22/CYP2D6 activity. It was found to promote nuclear translocation of Nrf2 and expression of NQO1 and Trx1 proteins. Since Cyp2d22/CYP2D6 inhibitor (ketoconazole/quinidine) per se reduced Cyp2d22/CYP2D6 activity and dopamine content, it was found to substantially increase the pesticides-induced reduction in Cyp2d22/CYP2D6 activity and dopamine content. Inhibitors normalized the pesticides induced changes in Nrf2 translocation and NQO1 and Trx1 levels in pesticides treated groups. CONCLUSION: The results suggest that resveratrol promotes the catalytic activity of xenobiotic metabolizing enzyme, Cyp2d22/CYP2D6, which partially contributes to Nrf2 activation in pesticides- induced Parkinsonism.

Silymarin Protects Against Impaired Autophagy Associated with 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Induced Parkinsonism.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exacerbates mitochondrial impairment and α-synuclein expression leading to Parkinsonism. Impaired mitochondria and over-expressed α-synuclein are degraded and eliminated via macroautophagy and chaperone-mediated autophagy. Owing to multiple properties, silymarin protects from oxidative stress-mediated cellular injury. However, its effect on MPTP-induced changes in autophagy is not yet known. The study aimed to decipher the effect of silymarin on MPTP-induced changes in autophagy. Male mice (20-25 g) were treated with silymarin (intraperitoneally, daily, 40 mg/kg) for 2 weeks. On day 7, a few animals were also administered with MPTP (intraperitoneally, 20 mg/kg, 4 injections at 2-h interval) along with vehicles. Striatal dopamine content was determined. Western blot analysis was done to assess α-synuclein, beclin-1, sequestosome, phosphorylated 5' adenosine monophosphate-activated protein kinase (p-AMPK), lysosome-associated membrane protein-2 (LAMP-2), heat shock cognate-70 (Hsc-70), LAMP-2A, phosphorylated unc-51-like autophagy activating kinase (p-Ulk1), and phosphorylated mechanistic target of rapamycin (p-mTOR) levels in the nigrostriatal tissue. Silymarin rescued from MPTP-induced increase in beclin-1, sequestosome, p-AMPK, and p-Ulk1 and decrease in LAMP-2, p-mTOR, and LAMP-2A levels. Silymarin defended against MPTP-induced increase in α-synuclein and reduction in dopamine content. The results demonstrate that silymarin protects against MPTP-induced changes in autophagy leading to Parkinsonism.

Malfunctioning of Chaperone-Mediated Autophagy in Parkinson's Disease: Feats, Constraints, and Flaws of Modulators.

Homeostatic regulation of class II programmed cell death/autophagy for the degradation and elimination of substandard organelles and defective proteins is decisive for the survival of dopaminergic neurons. Chaperone-mediated autophagy (CMA), one of the most highly dedicated self-sacrificing events, is accountable for the partial elimination of redundant soluble cytoplasmic proteins in Parkinson's disease (PD). CMA is characterized by the selective delivery of superfluous protein containing lysine-phenylalanine-glutamate-arginine-glutamine (KFERQ)/KFERQ-like motif to the lysosome through molecular chaperones, such as heat shock cognate-70 (Hsc-70). KFERQ/KFERQ-like motif present in the poor quality cytoplasmic substrate protein and Hsc-70 complex is recognized by a janitor protein, which is referred to as the lysosome-associated membrane protein-2A (LAMP-2A). This protein is known to facilitate an entry of substrate-chaperone complex in the lumen for hydrolytic cleavage of substrate and elimination of end-products. Impaired CMA is repeatedly blamed for an accumulation of surplus soluble proteins. However, it is still an enigma if CMA is a bonus or curse for PD. Case-control studies and cellular and animal models have deciphered the contribution of impaired CMA in PD. Current article updates the role of CMA in toxicant models and recapitulates the evidences that have highlighted a link between impaired CMA and PD. Although PD is an irreversible happening and CMA is a dual edging phenomenon, it is anticipated that fine-tuning of the latter encounters the former to a certain extent. Besides, the truth, embellishment, and propaganda regarding the issue are also emphasized in the final segment of the article.

Coherent and Contradictory Facts, Feats and Fictions Associated with Metal Accumulation in Parkinson's Disease: Epicenter or Outcome, Yet a Demigod Question.

Unwarranted exposure due to liberal use of metals for maintaining the lavish life and to achieve the food demand for escalating population along with an incredible boost in the average human life span owing to orchestrated progress in rejuvenation therapy have gradually increased the occurrence of Parkinson's disease (PD). Etiology is albeit elusive; association of PD with metal accumulation has never been overlooked due to noteworthy similitude between metal-exposure symptoms and a few cardinal features of disease. Even though metals are entailed in the vital functions, a hysterical shift, primarily augmentation, escorts the stern nigrostriatal dopaminergic neurodegeneration. An increase in the passage of metals through the blood brain barrier and impaired metabolic activity and elimination system could lead to metal accumulation in the brain, which eventually makes dopaminergic neurons quite susceptible. In the present article, an update on implication of metal accumulation in PD/Parkinsonism has been provided. Moreover, encouraging and paradoxical facts and fictions associated with metal accumulation in PD/Parkinsonism have also been compiled. Systematic literature survey of PD is performed to describe updated information if metal accumulation is an epicenter or merely an outcome. Finally, a perspective on the association of metal accumulation with pesticide-induced Parkinsonism has been explained to unveil the likely impact of the former in the latter.