title: Diquat causes caspase-independent cell death in SH-SY5Y cells by production of ROS independently of mitochondria.
abstract: Evidence indicates that Parkinson's disease (PD), in addition to having a genetic aetiology, has an environmental component that contributes to disease onset and progression. The exact nature of any environmental agent contributing to PD is unknown in most cases. Given its similarity to paraquat, an agrochemical removed from registration in the EU for its suspected potential to cause PD, we have investigated the in vitro capacity of the related herbicide Diquat to cause PD-like cell death. Diquat showed greater toxicity towards SH-SY5Y neuroblastoma cells and human midbrain neural cells than paraquat and also MPTP, which was independent of dopamine transporter-mediated uptake. Diquat caused cell death independently of caspase activation, potentially via RIP1 kinase, with only a minor contribution from apoptosis, which was accompanied by enhanced reactive oxygen species production in the absence of major inhibition of complex I of the mitochondrial respiratory chain. No changes in α-synuclein expression were observed following 24-h or 4-week exposure. Diquat may, therefore, kill neural tissue by programmed necrosis rather than apoptosis, reflecting the pathological changes seen following high-level exposure, although its ability to promote PD is unclear.
authors.affiliation: The Medical Toxicology Centre, and NIHR HPRU in Chemical and Radiation Threats and Hazards, Wolfson Building, Newcastle University, Claremont Place, Newcastle upon Tyne, Tyne and Wear, NE2 4AA, UK.
authors.forename: R
authors.initials: R
authors.lastname: Nisar
authors.affiliation: The Medical Toxicology Centre, and NIHR HPRU in Chemical and Radiation Threats and Hazards, Wolfson Building, Newcastle University, Claremont Place, Newcastle upon Tyne, Tyne and Wear, NE2 4AA, UK.
authors.forename: P S
authors.initials: PS
authors.lastname: Hanson
authors.affiliation: Mitochondrial Research Group, Institute of Neuroscience, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, Tyne and Wear, NE2 4HH, UK.
authors.forename: L
authors.initials: L
authors.lastname: He
authors.affiliation: Mitochondrial Research Group, Institute of Neuroscience, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, Tyne and Wear, NE2 4HH, UK.
authors.forename: R W
authors.initials: RW
authors.lastname: Taylor
authors.affiliation: The Medical Toxicology Centre, and NIHR HPRU in Chemical and Radiation Threats and Hazards, Wolfson Building, Newcastle University, Claremont Place, Newcastle upon Tyne, Tyne and Wear, NE2 4AA, UK.
authors.forename: P G
authors.initials: PG
authors.lastname: Blain
authors.affiliation: The Medical Toxicology Centre, and NIHR HPRU in Chemical and Radiation Threats and Hazards, Wolfson Building, Newcastle University, Claremont Place, Newcastle upon Tyne, Tyne and Wear, NE2 4AA, UK. c.m.morris@ncl.ac.uk.
authors.forename: C M
authors.initials: CM
authors.lastname: Morris
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D004178:Diquat / Q000633:toxicity*; D006540:Herbicides / Q000633:toxicity*; D006801:Humans; D020267:MPTP Poisoning / Q000473:pathology; D008928:Mitochondria / Q000378:metabolism; D009336:Necrosis / Q000139:chemically induced; D058953:Neural Stem Cells / Q000187:drug effects / Q000473:pathology; D009447:Neuroblastoma / Q000473:pathology; D010269:Paraquat / Q000633:toxicity; D017382:Reactive Oxygen Species / Q000378:metabolism*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D013997:Time Factors
chemical_list: D006540:Herbicides; D017382:Reactive Oxygen Species; D004178:Diquat; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D010269:Paraquat
keywords: Apoptosis; Diquat; Mitochondria; Necrosis; Parkinson’s disease; Pesticide