Local Gastrointestinal Injury Exacerbates Inflammation and Dopaminergic Cell Death in Parkinsonian Mice

Gil-Martínez, Ana-Luisa; Estrada, Cristina; Cuenca, Lorena; Cano, Juan Antonio; Valiente, Manuel; Martínez-Cáceres, Carlos-Manuel; Fernández-Villalba, Emiliano; Herrero, M.T.

doi:10.1007/s12640-019-0010-z

Cited by 9 publications

(6 citation statements)

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“…The obtained data reinforces the activation of microglial related-events together with the exacerbation of the dopaminergic neurodegeneration 7 . Together with these observations, in our previous study, we showed an exacerbation of the dopaminergic neuronal death and the glial activation both in the SNpc and striatum when combining MPTP and DSS intoxications 8 .…”

Section: Introductionsupporting

confidence: 85%

“…We aimed to elucidate in depth the molecular and cellular mechanisms triggered after a systemic insult in the striatum of mice untreated and treated with MPTP. The importance of specifically studying the effect of both toxins in the striatum is based on previous data obtained by immunohistochemical techniques in which we observed exacerbation of the inflammatory events when combining both toxins 8 . The results from this study provide novel information about the DEGs in the striatum of mice intoxicated only with DSS.…”

Section: Discussionmentioning

confidence: 99%

“…1 a). On day 8, mice were sacrificed by decapitation and brains were immediately removed and dissected into striatum and midbrain 8 . Samples were correctly stored depending on their future use.…”

Section: Methodsmentioning

confidence: 99%

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Identification of differentially expressed genes profiles in a combined mouse model of Parkinsonism and colitis

Gil-Martínez

Cuenca‐Bermejo

González-Cuello

et al. 2020

Sci Rep

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Different cellular mechanisms have been described as being potentially involved in the progression of neurodegeneration in Parkinson's disease, although their role is still unclear. The present study aimed to identify in detail, through differentially expressed genes analysis by bioinformatics approaches, the molecular mechanisms triggered after a systemic insult in parkinsonian mice. To address this objective, we combined a dextran sodium sulfate (DSS)-induced ulcerative colitis experimental mice model with an acute 1-methyl-4-phenyl-1,2,3,6-tetradropyridine (MPTP) intoxication. The animals were divided into four experimental groups based on the different treatments: (i) control, (ii) DSS, (iii) MPTP and (iv) MPTP + DSS. The data obtained by microarray and functional enrichment analysis point out the implication of different molecular mechanisms depending on the experimental condition. We see, in the striatum of animals intoxicated only with DSS, dysfunction processes related to the blood. On the other hand, oxidative stress processes are more prominent at the MPTP intoxicated mice. Finally, differentially expressed genes within the MPTP + DSS show functional enrichment in inflammation and programmed cell death. Interestingly, we identify a significant synergistic negative effect of both toxins since the expression of differentially expressed genes (DEGs) related to balanced cellular homeostasis was not enough to prevent processes associated with cell death. This work provides detailed insights into the involvement of systemic inflammation, triggered after an insult in the colon, in the progression of the degeneration in Parkinsonism. In this way, we will be able to identify promising therapeutic targets that prevent the contribution of inflammatory processes in the progression of Parkinson's disease. Parkinson's disease (PD) is the second most common age-related neurodegenerative disorder following Alzheimer's disease. The main pathological feature of PD is the progressive loss of dopaminergic neurons in the Substantia Nigra pars compacta (SNpc), with the subsequent loss of dopamine (DA) in the striatum. Although much uncertainty still exists about the aetiology of PD, available evidence suggests the implication of numerous processes such as oxidative stress, mitochondrial dysfunction, inflammation and cell apoptosis. Specifically, the deleterious role of systemic inflammation in the onset and progression of PD is becoming evident, so that the interest in its study has increased in the last years 1. In this sense, it is showed that dopaminergic neurons are more vulnerable to oxidative stress and pro-inflammatory cytokines because of their low levels of intracellular glutathione concentrations 2. Thus, a sustained systemic or brain inflammation involves activated microglia cells that secrete pro-inflammatory factors that damage neurons 3. At the same time, damaged neurons release toxic factors that recruit more glial cells, resulting in a fatal vicious cycle.

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Section: Introductionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

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Identification of differentially expressed genes profiles in a combined mouse model of Parkinsonism and colitis

Gil-Martínez

Cuenca‐Bermejo

González-Cuello

et al. 2020

Sci Rep

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“…Importantly, a few recent studies have reported that colitis is sufficient to induce alterations in the dopaminergic nigrostriatal pathway. A reduction in expression of tyrosine hydroxylase (TH), the rate limiting enzyme in dopamine synthesis, in the SN was observed in a study using acute DSS alone 100 ; however, DSS in conjunction with the neurotoxin MPTP, resulted in enhanced reduction of TH expression in the SN, as well as increases in Iba1+ cells and GFAP+ cells, suggestive of a degenerative phenotype with astrogliosis and increased microglial activation 100 . In a separate study examining different paradigms of DSS induction, it has been reported that an acute model is sufficient to increase nigral IL-1β, suggesting alterations in the inflammatory state of the SN, but insufficient to produce nigrostriatal degenerative phenotypes.…”

Section: Evidence Linking Colitis and Pd-associated Neuropathology In Animal Modelsmentioning

confidence: 99%

Is LRRK2 the missing link between inflammatory bowel disease and Parkinson’s disease?

Herrick

Tansey

2021

npj Parkinsons Dis.

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Links that implicate the gastrointestinal system in Parkinson’s disease (PD) pathogenesis and progression have become increasingly common. PD shares several similarities with Crohn’s disease (CD). Intestinal inflammation is common in both PD and CD and is hypothesized to contribute to PD neuropathology. Mutations in leucine-rich repeat kinase 2 (LRRK2) are one of the greatest genetic contributors to PD. Variants in LRRK2 have also been associated with increased incidence of CD. Since its discovery, LRRK2 has been studied intensely in neurons, despite multiple lines of evidence showing that LRRK2 is highly expressed in immune cells. Based on the fact that higher levels of LRRK2 are detectable in inflamed colonic tissue from CD patients and in peripheral immune cells from sporadic PD patients relative to matched controls, we posit that LRRK2 regulates inflammatory processes. Therefore, LRRK2 may sit at a crossroads whereby gut inflammation and higher LRRK2 levels in CD may be a biomarker of increased risk for sporadic PD and/or may represent a tractable therapeutic target in inflammatory diseases that increase risk for PD. Here we will focus on reviewing how PD and CD share overlapping phenotypes, particularly in terms of LRRK2 in the context of the immune system, that could be targeted in future therapies.

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“…Differentially expressed genes within the MPTP+DSS show functional enrichment in inflammation and programmed cell death and both toxins have a significant synergistic negative effect. Similarly, another study using MPTP+DSS mice showed significant decrease of dopaminergic neurons and dopaminergic fibers, suggesting that intestinal inflammation is able to exacerbate death of dopaminergic neurons through inducing system inflammation [ 148 ].…”

Section: Intestinal Dysfunctions In Pdmentioning

confidence: 99%

Intestinal Inflammation and Parkinson’s Disease

Li¹,

Chen²,

Jiang³

et al. 2021

Aging and disease

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Local Gastrointestinal Injury Exacerbates Inflammation and Dopaminergic Cell Death in Parkinsonian Mice

Cited by 9 publications

References 50 publications

Identification of differentially expressed genes profiles in a combined mouse model of Parkinsonism and colitis

Identification of differentially expressed genes profiles in a combined mouse model of Parkinsonism and colitis

Is LRRK2 the missing link between inflammatory bowel disease and Parkinson’s disease?

Intestinal Inflammation and Parkinson’s Disease

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