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

Abstract

SUMMARYExposure 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.

Parkinson's disease, aging and adult neurogenesis: Wnt/β‐catenin signalling as the key to unlock the mystery of endogenous brain repair

“…Conversely, DAergic neurotoxins, aging, inflammation, stress and chronic exposure to certain toxins or drugs decrease the generation of new neurons (Chandel et al, ; Das, Gangwal, Damre, Sangamwar, & Sharma, ; Hain et al, ; Iwata et al, ; Klein et al, ; L'Episcopo et al, , , ; Marchetti & Pluchino, ; van Praag et al, ; Seib & Martin‐Villalba, ; Sung, ; Veena et al, ; Villeda et al, ). NSCs are extremely vulnerable to a wide range of insults and toxic exposures, such as the neurotoxicants used in experimental models of basal ganglia injury (Cintha et al, ; He et al, ; He, Uetsuka, & Nakayama, ; L'Episcopo et al, ; Shibui et al, ). Remarkably, exposure to the herbicide paraquat, which is associated with an increased risk of idiopathic PD, results in a pro‐inflammatory senescence‐associated secretory phenotype capable of damaging neuronal, glial and NSC cells, and therefore likely contributing to DAergic neurodegeneration (Chinta et al, ).…”

Targeting Aged Astrocytes May Be a New Therapeutic Strategy in Parkinson's Disease

“…It is therefore possible that cell senescence contributes to its pathophysiology. In a recent article in Cell Reports , Chinta and colleagues have shown that astrocytes exhibiting an age‐associated (senescent) phenotype are toxic to neurons in vitro, and their removal is associated with better outcomes in a mouse model of PD. This finding may be relevant to other neurodegenerative conditions, such as Alzheimer's and amyotrophic lateral sclerosis, in which cellular senescence is also implicated …”

“…In postmortem tissue from the substantia nigra of 5 PD patients and 5 controls, Chinta and colleagues show that PD astrocytes have higher expression of senescence markers and elevated levels of inflammatory cytokines and metalloproteinases associated with a senescence‐associated “secretory” phenotype. In human cell culture models, astrocytes and fibroblasts show a more senescent phenotype when exposed to paraquat, a herbicide associated with PD risk, and this is associated with the production of factors, including IL‐6, which are toxic to dopaminergic neurons.…”

“…In human cell culture models, astrocytes and fibroblasts show a more senescent phenotype when exposed to paraquat, a herbicide associated with PD risk, and this is associated with the production of factors, including IL‐6, which are toxic to dopaminergic neurons. In a mouse model in which senescent astrocytes are selectively depleted, neurodegeneration is attenuated in response to paraquat, with better performance on motor tasks and decreased nigral dopaminergic cell loss …”

“… Lamin B1 levels (green; marker of senescence) are decreased in astrocytes (Glial fibrillary acidic protein (GFAP) + cells) in PD brain. Figure B from Chinta et al [Color figure can be viewed at http://wileyonlinelibrary.com]…”