Environmental neurotoxicants and inflammasome activation in Parkinson’s disease – A focus on the gut-brain axis

Johnson, Aishwarya Mary; Ou, Zhen-Yi Andy; Gordon, Richard D.; Saminathan, Hariharan

doi:10.1016/j.biocel.2021.106113

Cited by 8 publications

(8 citation statements)

References 174 publications

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“…Though the mechanisms of dopaminergic degeneration through PFAS exposure have not been deeply investigated, inflammasome activation is a potential therapeutic target for Parkinson’s disease. It was proposed that the inflammasomes could activate NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) upon sensing dysbiosis within the gut microbiome and host immunometabolic disruption induced by toxicants, and eventually lead to neuronal dysfunction [ 24 , 103 , 104 ]. Again, this is an unexplored area that could provide important insights into the gut–brain axis of people with Parkinson’s disease.…”

Section: Polyfluoroalkyl Substancesmentioning

confidence: 99%

Interaction between Per- and Polyfluorinated Substances (PFAS) and Acetaminophen in Disease Exacerbation—Focusing on Autism and the Gut–Liver–Brain Axis

Jiang,

Guo

2024

Toxics

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This review presents a new perspective on the exacerbation of autism spectrum disorder (ASD) by per- and polyfluoroalkyl substances (PFAS) through the gut–liver–brain axis. We have summarized evidence reported on the involvement of the gut microbiome and liver inflammation that led to the onset and exacerbation of ASD symptoms. As PFAS are toxicants that particularly target liver, this review has comprehensively explored the possible interaction between PFAS and acetaminophen, another liver toxicant, as the chemicals of interest for future toxicology research. Our hypothesis is that, at acute dosages, acetaminophen has the ability to aggravate the impaired conditions of the PFAS-exposed liver, which would further exacerbate neurological symptoms such as lack of social communication and interest, and repetitive behaviors using mechanisms related to the gut–liver–brain axis. This review discusses their potential interactions in terms of the gut–liver–brain axis and signaling pathways that may contribute to neurological diseases.

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Section: Polyfluoroalkyl Substancesmentioning

confidence: 99%

Interaction between Per- and Polyfluorinated Substances (PFAS) and Acetaminophen in Disease Exacerbation—Focusing on Autism and the Gut–Liver–Brain Axis

Jiang,

Guo

2024

Toxics

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“…The dysbiosis of intestinal microbiota can lead to intestinal inflammation, which can initiate the accumulation of misfolded α-synuclein in ENS in the early stage, and activate microglia and astrocytes through the microbiota-gut-brain axis upward pathway, thus triggering and/or promoting CNS inflammation and neurodegeneration. The above mechanism can have a synergistic effect with genetic and environmental factors to jointly trigger and promote the occurrence and development of PD ( 82 , 83 ). Rota et al found that in α-synuclein transgenic mice, significant symptoms of gastrointestinal dysfunction (such as constipation) precede CNS neurodegeneration ( 84 ).…”

Section: Intestinal Microbiome Dysregulation and Intestinal Inflammationmentioning

confidence: 99%

The role of the microbiota-gut-brain axis and intestinal microbiome dysregulation in Parkinson’s disease

Meng

Chen

et al. 2023

Front. Neurol.

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Parkinson’s disease (PD) is a complex progressive neurodegenerative disease associated with aging. Its main pathological feature is the degeneration and loss of dopaminergic neurons related to the misfolding and aggregation of α-synuclein. The pathogenesis of PD has not yet been fully elucidated, and its occurrence and development process are closely related to the microbiota-gut-brain axis. Dysregulation of intestinal microbiota may promote the damage of the intestinal epithelial barrier, intestinal inflammation, and the upward diffusion of phosphorylated α-synuclein from the enteric nervous system (ENS) to the brain in susceptible individuals and further lead to gastrointestinal dysfunction, neuroinflammation, and neurodegeneration of the central nervous system (CNS) through the disordered microbiota-gut-brain axis. The present review aimed to summarize recent advancements in studies focusing on the role of the microbiota-gut-brain axis in the pathogenesis of PD, especially the mechanism of intestinal microbiome dysregulation, intestinal inflammation, and gastrointestinal dysfunction in PD. Maintaining or restoring homeostasis in the gut microenvironment by targeting the gut microbiome may provide future direction for the development of new biomarkers for early diagnosis of PD and therapeutic strategies to slow disease progression.

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“…Individuals in certain high-risk occupations, such as farmers, have up to a 16% higher rate of PD occurrence compared to the general population [ 69 ]. The use of various pesticides and their link to PD and its progression have been previously reviewed [ 19, 70, 71 ]. Treatment with Mn results in impaired mitochondria function in microglia cells, leading to inflammasome activation [ 35 ].…”

Section: Triggers and Drivers Of Persistent Inflammasome Activation I...mentioning

confidence: 99%

“…However, antibodies associated with these inflammasome markers have been sub-par, generating unreliable results in terms of being able to differentiate the proteolytically active forms from the inactive pro-forms. Additionally, there is currently no way to determine if the elevated inflammasome markers observed in PD patients are a result of NLRP3 activation or if they are generated through other inflammasomes which could be relevant to PD [ 19 ].…”

Section: Therapeutic Targeting Of Inflammasomes For Disease Modificat...mentioning

confidence: 99%

“…Importantly, inflammasome activation appears to 179 be a common underlying theme in all pre-clinical PD models irrespective of the different pathological triggers used to initiate these models ranging from ␣-synuclein aggregates, dopaminergic neurotoxicants such as 1-methyl-4-phenyl-1,2,3,6-tetrahrdyopyridine (MPTP) or PD-linked environmental chemicals such as paraquat (PQ) or manganese (Mn)[12,19]. These findings have emerged from independent studies across multiple research groups, providing credence to the inflammasome activation paradigm in multiple PD models.…”

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confidence: 99%

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Inflammasome Activation in Parkinson’s Disease

Jewell

Herath

Gordon

2022

JPD

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Chronic sterile inflammation and persistent immune activation is a prominent pathological feature of Parkinson’s disease (PD). Inflammasomes are multi-protein intracellular signaling complexes which orchestrate inflammatory responses in immune cells to a diverse range of pathogens and host-derived signals. Widespread inflammasome activation is evident in PD patients at the sites of dopaminergic degeneration as well as in blood samples and mucosal biopsies. Inflammasome activation in the nigrostriatal system is also a common pathological feature in both neurotoxicant and α-synuclein models of PD where dopaminergic degeneration occurs through distinct mechanisms. The NLRP3 (NLR Family Pyrin Domain Containing 3) inflammasome has been shown to be the primary driver of inflammatory neurotoxicity in PD and other neurodegenerative diseases. Chronic NLRP3 inflammasome activation is triggered by pathogenic misfolded α-synuclein aggregates which accumulate and spread over the disease course in PD. Converging lines of evidence suggest that blocking inflammasome activation could be a promising therapeutic strategy for disease modification, with both NLRP3 knockout mice and CNS-permeable pharmacological inhibitors providing robust neuroprotection in multiple PD models. This review summarizes the current evidence and knowledge gaps around inflammasome activation in PD, the pathological mechanisms by which persistent inflammasome activation can drive dopaminergic degeneration and the therapeutic opportunities for disease modification using NLRP3 inhibitors.

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Environmental neurotoxicants and inflammasome activation in Parkinson’s disease – A focus on the gut-brain axis

Cited by 8 publications

References 174 publications

Interaction between Per- and Polyfluorinated Substances (PFAS) and Acetaminophen in Disease Exacerbation—Focusing on Autism and the Gut–Liver–Brain Axis

Interaction between Per- and Polyfluorinated Substances (PFAS) and Acetaminophen in Disease Exacerbation—Focusing on Autism and the Gut–Liver–Brain Axis

The role of the microbiota-gut-brain axis and intestinal microbiome dysregulation in Parkinson’s disease

Inflammasome Activation in Parkinson’s Disease

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