Cellular Senescence Is Induced by the Environmental Neurotoxin Paraquat and Contributes to Neuropathology Linked to Parkinson’s Disease

Chinta, Shankar J.; Woods, Georgia; Demaria, Marco; Rane, Anand; Zou, Ying; McQuade, Amanda; Rajagopalan, Subramanian; Limbad, Chandani; Madden, David T.; Campisi, Judith; Andersen, Julie K.

doi:10.1016/j.celrep.2017.12.092

Cellular Senescence Is Induced by the Environmental Neurotoxin Paraquat and Contributes to Neuropathology Linked to Parkinson’s Disease

Journal Article · Mon Jan 01 00:00:00 EST 2018 · Cell Reports

DOI:https://doi.org/10.1016/j.celrep.2017.12.092· OSTI ID:1623642

Chinta, Shankar J. ^[1]; Woods, Georgia ^[2]; Demaria, Marco ^[2]; Rane, Anand ^[2]; Zou, Ying ^[2]; McQuade, Amanda ^[2]; Rajagopalan, Subramanian ^[2]; Limbad, Chandani ^[3]; Madden, David T. ^[4]; Campisi, Judith ^[5]; Andersen, Julie K. ^[2]

Buck Inst. for Research on Aging, Novato, CA (United States); Touro Univ. California, Vallejo, CA (United States). College of Pharmacy; DOE/OSTI
Buck Inst. for Research on Aging, Novato, CA (United States)
Buck Inst. for Research on Aging, Novato, CA (United States); Univ. of California, Berkeley, CA (United States). Comparative Biochemistry Graduate Program
Buck Inst. for Research on Aging, Novato, CA (United States); Touro Univ. California, Vallejo, CA (United States). College of Pharmacy
Buck Inst. for Research on Aging, Novato, CA (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)

Exposure to the herbicide paraquat (PQ) is associated with an increased risk of idiopathic Parkinson’s disease (PD). Therapies based on PQ’s presumed mechanisms of action have not, however, yielded effective disease therapies. Cellular senescence is an anticancer mechanism that arrests proliferation of replication-competent cells and results in a pro-inflammatory senescence associated secretory phenotype (SASP) capable of damaging neighboring tissues. Here, we demonstrate that senescent cell markers are preferentially present within astrocytes in PD brain tissues. Additionally, PQ was found to induce astrocytic senescence and an SASP in vitro and in vivo, and senescent cell depletion in the latter protects against PQ-induced neuropathology. Our data suggest that exposure to certain environmental toxins promotes accumulation of senescent cells in the aging brain, which can contribute to dopaminergic neurodegeneration. Therapies that target senescent cells may constitute a strategy for treatment of sporadic PD, for which environmental exposure is a major risk factor.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1623642

Journal Information:: Cell Reports, Journal Name: Cell Reports Journal Issue: 4 Vol. 22; ISSN 2211-1247

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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Ageing as a risk factor for neurodegenerative disease Hou, Yujun; Dan, Xiuli; Babbar, Mansi Nature Reviews Neurology, Vol. 15, Issue 10 https://doi.org/10.1038/s41582-019-0244-7	journal	September 2019
From discoveries in ageing research to therapeutics for healthy ageing Campisi, Judith; Kapahi, Pankaj; Lithgow, Gordon J. Nature, Vol. 571, Issue 7764 https://doi.org/10.1038/s41586-019-1365-2	journal	July 2019
Senolytic therapy alleviates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model Zhang, Peisu; Kishimoto, Yuki; Grammatikakis, Ioannis Nature Neuroscience, Vol. 22, Issue 5 https://doi.org/10.1038/s41593-019-0372-9	journal	April 2019
Astrocyte Support for Oligodendrocyte Differentiation can be Conveyed via Extracellular Vesicles but Diminishes with Age Willis, Cory M.; Nicaise, Alexandra M.; Bongarzone, Ernesto R. Scientific Reports, Vol. 10, Issue 1 https://doi.org/10.1038/s41598-020-57663-x	journal	January 2020
Cardiac glycosides are broad-spectrum senolytics Guerrero, Ana; Herranz, Nicolás; Sun, Bin Nature Metabolism, Vol. 1, Issue 11 https://doi.org/10.1038/s42255-019-0122-z	journal	October 2019
Paraquat and Parkinson’s disease: a systematic review and meta-analysis of observational studies Vaccari, Carolina; El Dib, Regina; Gomaa, Huda Journal of Toxicology and Environmental Health, Part B, Vol. 22, Issue 5-6 https://doi.org/10.1080/10937404.2019.1659197	journal	August 2019
Upregulation of the p53-p21 pathway by G2019S LRRK2 contributes to the cellular senescence and accumulation of α-synuclein Ho, Dong Hwan; Seol, Wongi; Son, Ilhong Cell Cycle, Vol. 18, Issue 4 https://doi.org/10.1080/15384101.2019.1577666	journal	February 2019
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Astragaloside IV inhibits astrocyte senescence: implication in Parkinson’s disease Xia, Mei-Ling; Xie, Xia-Hong; Ding, Jian-Hua Journal of Neuroinflammation, Vol. 17, Issue 1 https://doi.org/10.1186/s12974-020-01791-8	journal	April 2020
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Astrocyte Support for Oligodendrocyte Differentiation can be Conveyed via Extracellular Vesicles but Diminishes with Age. Willis, Cory; Nicaise, Alexandra; Bongarzone, Ernesto R. Apollo - University of Cambridge Repository https://doi.org/10.17863/cam.50979	text	January 2020
Astrocyte Support for Oligodendrocyte Differentiation can be Conveyed via Extracellular Vesicles but Diminishes with Age Willis, Cory M.; Nicaise, Alexandra M.; Bongarzone, Ernesto R. Apollo - University of Cambridge Repository https://doi.org/10.17863/cam.63622	text	January 2020
Re-thinking the Etiological Framework of Neurodegeneration Castillo, Ximena; Castro-Obregón, Susana; Gutiérrez-Becker, Benjamin Frontiers in Neuroscience, Vol. 13 https://doi.org/10.3389/fnins.2019.00728	journal	July 2019
Paraquat and Parkinson’s disease: a systematic review and meta-analysis of observational studies Vaccari, Carolina; Dib, Regina El; Gomaa, Huda Taylor & Francis https://doi.org/10.6084/m9.figshare.9761315.v1	text	January 2019

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