Objective: To understand the role of cellular senescence in brain aging and neurodegeneration in Parkinson’s disease models.

Background: Although cellular senescence has been causally linked to age-related pathologies outside the brain, little is known about its role in the brain aging, much less in age-related neurodegenerative diseases. Of recent interest, however, expression of the tumor suppressor and senescence marker p16INK4a and the SASP factor matrix metalloproteinase (MMP) 3 increased significantly in the brain during normal aging, and were even higher in affected cortical brain tissues from patients with Alzheimer’s disease. Here, we examined postmortem human brain tissue and found that the incidence of PD correlated with expression of senescence markers, suggesting that senescent cells may contribute to PD. To test this hypothesis, we examined cell culture and mouse models of PD for the presence of senescent cells. Importantly, using a mouse model in which senescent cells can be inducibly ablated, we studied the role of senescent cells in PD-associated phenotypes associated with systemic PQ exposure.

Methods: We used both cell culture and mouse models of PD to examine the role of cellular senescence in aging and neurodegeneration associated with PD.

Results: We show that pesticide PQ induces senescence in astrocytes, the most abundant proliferation-competent cells in the brain, in culture and in vivo. Importantly, using a genetic mouse model to eliminate senescent cells, we show that senescent cell ablation protects against PD-like neuropathologies after systemic PQ administration. Senescent cell markers increased following PQ administration, and were present in astrocytes in affected PD patient midbrain tissues.

Conclusions: Thus, cellular senescence can be induced following exposure to an environmental agent linked to PD, and removal of senescent cells can be neuroprotective. Therapies targeted at preventing cellular senescence or eliminating senescent cells may therefore constitute a novel therapeutic strategy for PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/cellular-senescence-induced-by-paraquat-drives-neuropathology-associated-with-parkinsons-disease/