Chronic stress-induced gut dysfunction exacerbates Parkinson's disease phenotype and pathology in a rotenone-induced mouse model of Parkinson's disease

Dodiya, Hemraj B.; Forsyth, Christopher B.; Voigt, Robin M.; Engen, Phillip A.; Patel, Jayvadan; Shaikh, Maliha; Green, Stefan J.; Naqib, Ankur; Roy, Avik; Kordower, Jeffrey H.; Pahan, Kalipada; Shannon, Kathleen M.; Keshavarzian, Ali

doi:10.1016/j.nbd.2018.12.012

Cited by 211 publications

(175 citation statements)

References 83 publications

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“…Chronic stress has been shown to alter gut motility and intestinal permeability. [50][51][52][53] Elevated levels of corticosterone have been shown to decrease motility and depress myenteric neuron function in the small intestine by reducing electrical stimulation-induced Ca 2+ responses, which are important for enteric neuron transmission and gut motility. 53 In our study, single-housed A53T mice had slower transit time and reduced colon motility when compared with grouphoused A53T mice, which could be contributed to by increased corticosterone levels, if corticosterone has inhibitory effects in the colon that are similar to those in the small intestine.…”

Section: Discussionmentioning

confidence: 99%

Chronic isolation stress is associated with increased colonic and motor symptoms in the A53T mouse model of Parkinson’s disease

Diwakarla

Finkelstein

Constable

et al. 2019

Neurogastroenterology Motil

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Background Chronic stress exacerbates motor deficits and increases dopaminergic cell loss in several rodent models of Parkinson's disease (PD). However, little is known about effects of stress on gastrointestinal (GI) dysfunction, a common non‐motor symptom of PD. We aimed to determine whether chronic stress exacerbates GI dysfunction in the A53T mouse model of PD and whether this relates to changes in α‐synuclein distribution. Methods Chronic isolation stress was induced by single‐housing WT and homozygote A53T mice between 5 and 15 months of age. GI and motor function were compared with mice that had been group‐housed. Key Results Chronic isolation stress increased plasma corticosterone and exacerbated deficits in colonic propulsion and whole‐gut transit in A53T mice and also increased motor deficits. However, our results indicated that the novel environment‐induced defecation response, a common method used to evaluate colorectal function, was not a useful test to measure exacerbation of GI dysfunction, most likely because of the reported reduced level of anxiety in A53T mice. A53T mice had lower corticosterone levels than WT mice under both housing conditions, but single‐housing increased levels for both genotypes. Enteric neuropathy was observed in aging A53T mice and A53T mice had a greater accumulation of alpha‐synuclein (αsyn) in myenteric ganglia under both housing conditions. Conclusions & Inferences Chronic isolation stress exacerbates PD‐associated GI dysfunction, in addition to increasing motor deficits. However, these changes in GI symptoms are not directly related to corticosterone levels, worsened enteric neuropathy, or enteric αsyn accumulation.

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Section: Discussionmentioning

confidence: 99%

Chronic isolation stress is associated with increased colonic and motor symptoms in the A53T mouse model of Parkinson’s disease

Diwakarla

Finkelstein

Constable

et al. 2019

Neurogastroenterology Motil

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“…High GM-CSF levels in AD patients brain parenchyma and cerebrospinal fluid lead to blood-brain barrier open [34] . It has also been reported that BBB disruption due to lower expression and disassembly of tight junction-related proteins happens in age-associated brain changes and other neurodegenerative diseases [35,36] .…”

Section: Discussionmentioning

confidence: 99%

TRA2A-induced upregulation of LINC00662 regulates blood-brain barrier permeability by affecting ELK4 mRNA stability in Alzheimer’s microenvironment

Liu

Zhu

Liu

et al. 2019

Preprint

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AbstractThe blood-brain barrier (BBB) has an important significance in maintenance and regulation of the neural microenvironment. The occurrence of BBB disruption is the pathological change of early Alzheimer’s disease (AD). RNA-binding proteins and long non-coding RNAs are closely related to the regulation of BBB permeability. Our study was performed to demonstrate TRA2A/LINC00662/ELK4 axis that regulates BBB permeability in AD microenvironment. In Aβ1-42-incubated microvascular endothelial cells (ECs) of BBB model in vitro, TRA2A and LINC00662 were enriched. TRA2A increased the stability of LINC00662 by binding with it. The knockdown of either TRA2A or LINC00662 decreased the BBB permeability via upregulating the levels of tight junction-related proteins. ELK4 was downregulated in BBB model in vitro in AD microenvironment. LINC00662 mediated the degradation of ELK4 mRNA by SMD pathway. The downregulated ELK4 increased the permeability of BTB by inducing the tight junction-related proteins. TRA2A/LINC00662/ELK4 axis is important in the regulation of BBB permeability in AD microenvironment, which would be a new molecular target for AD treatment.

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“…In rotenone models, chronic stress induces a deregulation of HPA which may culminate in dysbacteriosis, characterised by a significant reduction in the number of species belonging to the genus Bifidobacterium, to the detriment of Escherichia coli. Prolonged exposure leads to an increased intestinal permeability which creates a "leaky gut," dysosmia, and colitis by inducing specific neuroanatomical and neurochemical changes [55][56][57][58][59].…”

Section: The Relevance Of Gut Microflora In Parkinson's Disease Pathomentioning

confidence: 99%

Minireview on the Relations between Gut Microflora and Parkinson’s Disease: Further Biochemical (Oxidative Stress), Inflammatory, and Neurological Particularities

Ilie

Ciobîcă

McKenna

et al. 2020

Oxidative Medicine and Cellular Longevity

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The aetiology of Parkinson’s disease (PD) is a highly debated topic. Despite the progressive increase in the number of patients diagnosed with PD over the last couple of decades, the causes remain largely unknown. This report is aimed at highlighting the main features of the microbial communities which have been termed “the second brain” that may be a major participant in the etiopathophysiology of PD. It is possible that dysbiosis could be caused by an overactivity of proinflammatory cytokines which act on the gastrointestinal tract as well as infections. The majority of patients who are diagnosed with PD display gastrointestinal symptoms as one of the earliest features. In addition, an unbalanced cycle of oxidative stress caused by dysbacteriosis may have the effect of gradually promoting PD’s specific phenotype. Thus, it seems that bacteria possess the ability to manipulate the brain by initiating specific responses, defining their capability to configure the human body, with oxidative stress playing a pivotal role in preventing infections but also in activating related signalling pathways.

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Chronic stress-induced gut dysfunction exacerbates Parkinson's disease phenotype and pathology in a rotenone-induced mouse model of Parkinson's disease

Cited by 211 publications

References 83 publications

Chronic isolation stress is associated with increased colonic and motor symptoms in the A53T mouse model of Parkinson’s disease

Chronic isolation stress is associated with increased colonic and motor symptoms in the A53T mouse model of Parkinson’s disease

TRA2A-induced upregulation of LINC00662 regulates blood-brain barrier permeability by affecting ELK4 mRNA stability in Alzheimer’s microenvironment

Minireview on the Relations between Gut Microflora and Parkinson’s Disease: Further Biochemical (Oxidative Stress), Inflammatory, and Neurological Particularities

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