Glial autophagy capability and the control of neuroinflammatory signaling in Parkinson’s disease.

Abstract

Parkinson’s (PD) is caused by the progressive degeneration of dopaminergic neurons in the Substantia Nigra pars compacta (SNpc). Neuroinflammation influences progression of PD, with elevated pro-inflammatory cytokines observed in post-mortem human SNpc and restricted inflammation improving disease outcomes in animal models. There is building evidence to suggest that astrocytes modulate pathological neuroinflammation by dysfunctional homeostatic processes such as autophagy; however, the underpinning biology of mid-brain regional astrocytes is poorly understood. We have characterised the NLRP3 inflammasome response of human induced pluripotent stem cell (hiPSC) derived ventral midbrain astrocytes (vmAstros), in order to establish them as models for PD neuroinflammation research, and further investigated the role of autophagy in regulating this pathway. Our data reveal that vmAstros process IL-1Β in a manner independent from potassium ion efflux, a classical inducer of NLRP3 inflammasome activation. Instead, vmAstros activate the NLRP3 inflammasome in response to pro-inflammatory cytokines known to induce neurotoxic astrocyte reactivity. Inducing inflammation in vmAstros was also seen to induce autophagosome accumulation, and inhibition of autophagy resulted in decreased levels of pro-IL-1β in these cells. This reveals that autophagy plays a regulatory role in maintaining sufficient levels of pro-IL-1β in vmAstros following NLRP3 inflammasome activation, which occurs during neurotoxic astrocyte reactivity. This presents astrocyte reactivity and its interplay with cellular homeostatic process as an important part of mediating PD neuroinflammation, and warrants further study.

Date of Award	24 Jan 2023
Original language	English
Awarding Institution	University of Bristol
Supervisor	Jon D Lane (Supervisor) & Bernadette M Carroll (Supervisor)