Parkinson's disease: connecting mitochondria to inflammasomes

• Published in: Trends in immunology Vol. 43; no. 11; pp. 877 - 885
• Main Authors: Lawrence, Grace M.E.P., Holley, Caroline L., Schroder, Kate
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.11.2022; Elsevier Limited
• Subjects: Animals; Apoptosis; Brain research; Central nervous system; Dopaminergic Neurons - metabolism; Dopaminergic Neurons - pathology; Fission; Gene expression; Homeostasis; Humans; inflammasome; Inflammasomes; Inflammasomes - metabolism; Inflammation; Kinases; Mammals; Metabolism; Microglia; Mitochondria; Mitochondrial DNA; Molecular modelling; Movement disorders; Neuroblastoma; neurodegeneration; Neurodegenerative diseases; neuroinflammation; Neurons; Neurotoxicity; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; NLRP3; Oxidative stress; Parkinson Disease - pathology; Parkinson's; Parkinson's disease; Pathogenesis; Pathology; Patients; Phosphorylation; Proteins; neurodegeneration; Parkinson's; NLRP3; neuroinflammation; inflammation; inflammasome
• ISSN: 1471-4906; 1471-4981
• DOI: 10.1016/j.it.2022.09.010

Parkinson's disease (PD)-associated neurotoxins and mutations induce mitochondrial fission in vitro.Inducible mitochondrial fission promotes myeloid cell expression of proinflammatory mediators such as the inflammasome substrate pro-IL-1β.Emerging evidence highlights the microglial NLRP3 inflammasome as an important driver of PD pathology.Pharmacological inhibition of either mitochondrial fission or NLRP3 function has provided neuroprotective benefit in several rodent models of PD. The molecular links between idiopathic and familial cases of Parkinson's disease (PD) have long remained elusive. New insight into the interplay between mitochondrial fragmentation, neuroinflammation (e.g., NLRP3 inflammasome signaling), and PD neuropathology might offer patients putative disease-modifying treatment options. Activated microglia foster a neurotoxic, inflammatory environment in the mammalian central nervous system (CNS) that drives the pathology of neurodegenerative diseases including Parkinson's disease (PD). Moreover, mitochondrial fission promotes microglial inflammatory responses in vitro. Given that the NLRP3 inflammasome and mitochondria are central regulators of both inflammation and PD, we explore potential functions for the NLRP3 inflammasome and mitochondrial dynamics in PD. Specifically, we propose that inducible microglial mitochondrial fission can promote NLRP3-dependent neuroinflammation in hereditary and idiopathic PD. Further in-depth exploration of this topic can prompt valuable discoveries of the underlying molecular mechanisms of PD neuroinflammation, identify novel candidate anti-inflammatory therapeutics for PD, and ideally provide better outcomes for PD patients.