title: Paraquat, but not maneb, induces synucleinopathy and tauopathy in striata of mice through inhibition of proteasomal and autophagic pathways.
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.
authors.affiliation: Department of Biochemistry and Molecular and Cell Biology, Georgetown University Medical Center, Washington DC, United States of America.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Wills
authors.forename: Joel
authors.initials: J
authors.lastname: Credle
authors.forename: Adam W
authors.initials: AW
authors.lastname: Oaks
authors.forename: Valeriy
authors.initials: V
authors.lastname: Duka
authors.forename: Jae-Hoon
authors.initials: JH
authors.lastname: Lee
authors.forename: Jessica
authors.initials: J
authors.lastname: Jones
authors.forename: Anita
authors.initials: A
authors.lastname: Sidhu
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D016022:Case-Control Studies; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects; D005659:Fungicides, Industrial / Q000633:toxicity; D006540:Herbicides / Q000633:toxicity; D006801:Humans; D008297:Male; D008344:Maneb / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D010269:Paraquat / Q000633:toxicity*; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D024801:Tauopathies / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism
chemical_list: D005659:Fungicides, Industrial; D006540:Herbicides; D051844:alpha-Synuclein; D008344:Maneb; D046988:Proteasome Endopeptidase Complex; D010269:Paraquat