Role of TLR4 in the gut-brain axis in Parkinson’s disease: a translational study from men to mice

Perez‐Pardo, Paula; Dodiya, Hemraj B.; Engen, Phillip A.; Forsyth, Christopher B.; Huschens, Andrea M; Shaikh, Maliha; Voigt, Robin M.; Naqib, Ankur; Green, Stefan J.; Kordower, Jeffrey H.; Shannon, Kathleen M.; Garssen, Johan; Kraneveld, Aletta D.; Keshavarzian, Ali

doi:10.1136/gutjnl-2018-316844

Cited by 310 publications

(300 citation statements)

References 55 publications

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“…Based on this hypothesis, it has been suggested that αSyn aggregates may potentially spread from the gut (ENS) to the brain (CNS) as a prion‐like protein by cell‐to‐cell transfer . These assumptions seem to be consistent with the long‐reported nonmotor symptoms of PD patients, often occurring before the onset of motor symptoms, including olfactory impairment and gastrointestinal (GI) dysfunctions, such as constipation and colonic inflammation …”

Section: Microbiota‐gut‐brain Axismentioning

confidence: 85%

“…However, based on experimental evidences, hypothetical mechanisms have been proposed. Imbalances in the gut microbiota composition may overstimulate the innate immune system of the intestinal mucosa, possibly through Toll‐like receptor 4 activation, increasing the levels of oxidative stress in the gut. Oxidative stress may activate enteric neurons and enteric glial cells, contributing to misfolding and accumulation of αSyn in the ENS .…”

Section: Microbiota‐gut‐brain Axismentioning

confidence: 99%

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Gut Vibes in Parkinson's Disease: The Microbiota‐Gut‐Brain Axis

Bullich

Keshavarzian

Garssen

et al. 2019

Movement Disord Clin Pract

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Background The complexity of the pathogenic mechanisms underlying neurodegenerative disorders such as Parkinson's disease (PD) is attributable to multifactorial changes occurring at a molecular level, influenced by genetics and environmental interactions. However, what causes the main hallmarks of PD is not well understood. Recent data increasingly suggest that imbalances in the gut microbiome composition might trigger and/or exacerbate the progression of PD. Objective The present review aims to (1) report emerging literature showing changes in microbiota composition of PD patients compared to healthy individuals and (2) discuss how these changes may initiate and/or perpetuate PD pathology. Methods We analyzed 13 studies published from 2015 and included in this review. Altered microbial taxa were compiled in a detailed table summarizing bacterial changes in fecal/mucosal samples. The methodology was systematically reviewed across the articles and was also included in a table to facilitate comparisons between studies. Results Multiple studies found a reduction in short‐chain fatty‐acid–producing bacteria that can rescue neuronal damage through epigenetic mechanisms. Overall, the studies showed that changes in the gut microbiota composition might influence colonic inflammation, gut permeability, and α‐synuclein aggregation, contributing to the neurogenerative process. Conclusion Further studies with larger cohorts and high‐resolution sequencing methods are required to better define gut microbiota changes in PD. Furthermore, additional longitudinal studies are required to determine the causal link between these changes and PD pathogenesis as well as to study the potential of the intestinal microbiota as a biomarker.

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Section: Microbiota‐gut‐brain Axismentioning

confidence: 85%

Section: Microbiota‐gut‐brain Axismentioning

confidence: 99%

Gut Vibes in Parkinson's Disease: The Microbiota‐Gut‐Brain Axis

Bullich

Keshavarzian

Garssen

et al. 2019

Movement Disord Clin Pract

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“…The products of post-translational protein modifications in AD, PD and PrD favour apoptosis and necroptosis over AUT by (a) increasing the activation of apoptosis (e.g. by increasing MITO membrane permeability) and necroptosis, by chronic activation of TRL4 and TNFα receptors [216][217][218][219][220][221][222][223][224][225][226][227][228][229][230][231][232][233][234], (b) promoting moderate to high increases in cytosolic ROS concentrations and (c) attenuating AUT [42,62,[235][236][237][238][239][240]. In contrast to PD and AD, PrP SC -infected cells are more likely to respond with necroptosis and then apoptosis.…”

Section: Summary Of Similarities/differences In the Mechanistic Pathwmentioning

confidence: 99%

Autophagy and Cell Death in Alzheimer’s, Parkinson’s and Prion Diseases

Ribarič¹,

Ribarič²

2020

Programmed Cell Death

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Neurodegenerative brain disorders (NBD) impair brain cells' proteostasis with the accumulation of normal, mutant, misfolded or unfolded proteins in the endoplasmic reticulum (ER). The increased ER burden of these proteins elicits the unfolded protein response (UPR) and stimulates autophagy (AUT). In the short term, UPR and AUT attenuate ER's burden. With prolonged ER stress, the UPR changes from supporting cell survival to promoting apoptosis. The failure of the UPR, to meet the increased protein burden, leads to an increase in cytosolic protein accumulation that initially further stimulates AUT. Over time, the accumulated proteins in the cytosol undergo post-translational changes into toxic monomers and oligomers that repress AUT at multiple levels and promote cell death. This review describes the interlinked signalling pathways of AUT, apoptosis and necroptosis and their modulation by Alzheimer's, Parkinson's and prion diseases and outlines the pharmacological strategies for targeting AUT, apoptosis and necroptosis signalling pathways. 2 oligomers; their production is stimulated by chronic inflammation and increased reactive oxygen species (ROS) production. These monomers and oligomers repress AUT and trigger either apoptosis or necroptosis (Figure 1) [4, 6-8]. Autophagy changes in selected NBDAn efficient autophagy (AUT) delays or attenuates the progression of AD, PD and PrD [9][10][11][12]. A summary of AUT changes in selected NBD is shown in Figure 2. Post-translationally modified proteins (PTMP)-such as soluble amyloid β-peptide 42 with a single oxidised methionine residue at position 35 (Aβ42-MET35-OX) in Alzheimer's disease, alpha-synuclein oxidised on methionine residues (MET-OX-αSYN) in Parkinson's disease and oxidised, self-propagating infectious isoforms of prion protein (MET-OX-PRP Sc ) in prion diseases (PrD)-inhibit (a) AUT, in AD, PD and PrD, and also (b) mitochondrial (MITO) function [13-23]. MET-OX-PRP Sc indirectly damage MITO function. The normal prion protein (PrP c ) binds with

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“…Additionally, we chose LPS as the immune stimulant because: (1) intraperitoneal and/or intracranial administration of LPS in mice led to increased microglial activation, neuroinflammation, neuronal loss including loss of dopaminergic neurons in the substantia nigra in a mouse model of PD [8] , and cognitive and neurological deficits [36] ; (2) aged individuals show increased systemic levels of LPS in the bloodstream [37] , which are associated with increased inflammation and microglial activation [38] ; and (3) in humans, TLR4 activation is linked to age-related pathologies such as PD and AD [39][40][41] ; thus, LPS serves as a relevant aging-related physiological immune stimulant.…”

Section: Knockdown Of Phf15 Increases the Magnitude Of The Microglialmentioning

confidence: 99%

Phf15 - a novel transcriptional repressor regulating inflammation in a mouse microglial cell line

Muroy¹,

Timblin²,

Preininger³

et al. 2020

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How to cite this article: Muroy SE, Timblin GA, Preininger MK, Cedillo P, Saijo K. Phf15 -a novel transcriptional repressor regulating inflammation in mouse microglia cell line. Neuroimmunol Neuroinflammation 2020;7:166-82. http://dx. AbstractAim: Excessive microglial inflammation has emerged as a key player in mediating the effects of aging and neurodegeneration on brain dysfunction. Thus, there is great interest in discovering transcriptional repressors that can control this process. We aimed to examine whether Phf15 -one of the top differentially expressed genes in microglia during aging in humans -could regulate transcription of proinflammatory mediators in microglia. Methods:Real-time quantitative PCR was used to assess Phf15 mRNA expression in mouse brain during aging. Lossof-function [short hairpin RNA (shRNA) -mediated knockdown (KD) and CRISPR/Cas9-mediated knockout (KO) of Phf15 ] and gain-of-function [retroviral overexpression (OE) of murine Phf15 cDNA] studies in a murine microglial cell line (SIM-A9) followed by immune activation with lipopolysaccharide were used to determine the effect of Phf15 on proinflammatory factor (Tnfα , IL-1β , and Nos2 ) mRNA expression. RNA sequencing was used to determine global transcriptional changes after Phf15 knockout under basal conditions and after lipopolysaccharide stimulation.Results: Phf15 expression increases in mouse brain during aging, similar to humans. KD, KO, and OE studies determined that Phf15 represses mRNA expression levels of proinflammatory mediators such as Tnfα , IL-1β , and Nos2 . Global transcriptional changes after Phf15 KO showed that Phf15 specifically represses genes related to the antiviral (type I interferon) response and cytokine production in microglia. Conclusion:We provide the first evidence that Phf15 is an important transcriptional repressor of microglial inflammation, regulating the antiviral response and proinflammatory cytokine production. Importantly, Phf15 regulates both basal and signal-dependent activation and controls the magnitude and duration of the microglial inflammatory response.

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Role of TLR4 in the gut-brain axis in Parkinson’s disease: a translational study from men to mice

Cited by 310 publications

References 55 publications

Gut Vibes in Parkinson's Disease: The Microbiota‐Gut‐Brain Axis

Gut Vibes in Parkinson's Disease: The Microbiota‐Gut‐Brain Axis

Autophagy and Cell Death in Alzheimer’s, Parkinson’s and Prion Diseases

Phf15 - a novel transcriptional repressor regulating inflammation in a mouse microglial cell line

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