Abstract
SNCA and MAPT genes and environmental factors are important risk factors of Parkinson's disease [PD], the second-most common neurodegenerative disease. The agrichemicals maneb and paraquat selectively target dopaminergic neurons, leading to parkinsonism, through ill-defined mechanisms. In the current studies we have analyzed the ability of maneb and paraquat, separately and together, to induce synucleinopathy and tauopathy in wild type mice. Maneb was ineffective in increasing α-synuclein [α-Syn] or p-Tau levels. By contrast, paraquat treatment of mice resulted in robust accumulation of α-Syn and hyperphosphorylation of Tau in striata, through activation of p-GSK-3β, a major Tau kinase. Co-treatment with maneb did not enhance the effects of paraquat. Increased hyperacetylation of α-tubulin was observed in paraquat-treated mice, suggesting cytoskeleton remodeling. Paraquat, but not maneb, inhibited soluble proteasomal activity on a peptide substrate but this was not associated with a decreased expression of 26S proteasome subunits. Both paraquat and maneb treatments increased levels of the autophagy inhibitor, mammalian target of rapamycin, mTOR, suggesting impaired axonal autophagy, despite increases in certain autophagic proteins, such as beclin 1 and Agt12. Autophagic flux was also impaired, as ratios of LC3 II to LC3 I were reduced in treated animals. Increased mTOR was also observed in postmortem human PD striata, where there was a reduction in the LC3 II to LC3 I ratio. Heat shock proteins were either increased or unchanged upon paraquat-treatment suggesting that chaperone-mediated autophagy is not hampered by the agrichemicals. These studies provide novel insight into the mechanisms of action of these agrichemicals, which indicate that paraquat is much more toxic than maneb, via its inhibitory effects on proteasomes and autophagy, which lead to accumulation of α-Syn and p-Tau.
Highlights
Parkinson’s disease [PD] is the second-most common neurodegenerative disease, after Alzheimer’s disease
To assess if axonal autophagy is impaired in PD, we examined mTOR and major proteins involved in autophagosome formation in postmortem striata from PD patients and agematched non-diseased controls [N = 10–17 each]
The data presented here shows for the first time that paraquat induces a broad spectrum of pathological changes in striata which includes synucleinopathy, tauopathy, destabilization and hyperacetylation of microtubules, and inhibition of both proteasomal and autophagic pathways
Summary
Parkinson’s disease [PD] is the second-most common neurodegenerative disease, after Alzheimer’s disease. Epidemiological studies have linked agrichemicals to an increased risk of PD through rural living, farming, drinking well water, and exposure to agrichemicals used in these settings [1,2,3]. Several agrichemicals can selectively damage dopaminergic neurons, leading to the suggestion of an environmental basis for the development of sporadic PD [4,5]. Some reports have suggested that the toxicity of these agrichemicals is enhanced when used together, and animals treated with paraquat and maneb together showed synergistic reduction in motor activity and greater damage to both striatal nerve terminals and nigral cell bodies, relative to treatment with either agent alone [3,10,11,12]. Epidemiological studies have found increased risk for the development of PD upon exposure to both paraquat and maneb [13]
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