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

ObjectiveRecent evidence suggesting an important role of gut-derived inflammation in brain disorders has opened up new directions to explore the possible role of the gut-brain axis in neurodegenerative diseases. Given the prominence of dysbiosis and colonic dysfunction in patients with Parkinson’s disease (PD), we propose that toll-like receptor 4 (TLR4)-mediated intestinal dysfunction could contribute to intestinal and central inflammation in PD-related neurodegeneration.DesignTo test this hypothesis we performed studies in both human tissue and a murine model of PD. Inflammation, immune activation and microbiota composition were measured in colonic samples from subjects with PD and healthy controls subjects and rotenone or vehicle-treated mice. To further assess the role of the TLR4 signalling in PD-induced neuroinflammation, we used TLR4-knockout (KO) mice in conjunction with oral rotenone administration to model PD.ResultsPatients with PD have intestinal barrier disruption, enhanced markers of microbial translocation and higher pro-inflammatory gene profiles in the colonic biopsy samples compared with controls. In this regard, we found increased expression of the bacterial endotoxin-specific ligand TLR4, CD3+ T cells, cytokine expression in colonic biopsies, dysbiosis characterised by a decrease abundance of SCFA-producing colonic bacteria in subjects with PD. Rotenone treatment in TLR4-KO mice revealed less intestinal inflammation, intestinal and motor dysfunction, neuroinflammation and neurodegeneration, relative to rotenone-treated wild-type animals despite the presence of dysbiotic microbiota in TLR4-KO mice.ConclusionTaken together, these studies suggest that TLR4-mediated inflammation plays an important role in intestinal and/or brain inflammation, which may be one of the key factors leading to neurodegeneration in PD.

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Bilateral but not unilateral subthalamic stimulation promotes apathy: a translational study in rodents and Parkinson’s disease patients

10.1101/2020.06.11.147116 ◽

2020 ◽

Author(s):

Yvan Vachez ◽

Marie Bahout ◽

Robin Magnard ◽

Pierre-Maxime David ◽

Carole Carcenac ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Acute Effect ◽

Recent Experimental Data ◽

Translational Study ◽

Clinical Center ◽

Subthalamic Stimulation ◽

Operative Assessment ◽

Stn Dbs

ABSTRACTApathy is frequently reported in Parkinson’s disease (PD) patients under subthalamic nucleus deep brain stimulation (STN-DBS). The prevailing clinical view for apathy following STN-DBS is the reduction of dopaminergic medication. However, few clinical reports and recent experimental data suggested the pathogenicity of bilateral STN-DBS on motivation, challenging the leading opinion. Here, we investigate whether bilateralism of STN-DBS influences apathy outcome after STN-DBS, combining pre-clinical and clinical approaches. We assess the motivational effects of chronic unilateral STN-DBS in rats in the exact same conditions having highlighted a loss of motivation under bilateral STN-DBS. Clinical data are obtained by the follow-up of a cohort of parkinsonian patients undergoing unilateral STN-DBS and coming from the clinical center that described apathy related to bilateral STN-DBS itself. Despite an acute effect, which fades rapidly, unilateral STN-DBS did not induce a loss of motivation reminiscent to apathy in rats. In patients, apathy did not increase between the preoperative and the post-operative assessment. Together, those data demonstrate that bilateral but not unilateral STN-DBS can induce a loss of motivation in both rats and patients. This constitutes another evidence of the role of STN-DBS itself for apathy in PD.

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Immunomodulatory role of Parkinson’s disease 7 in inflammatory bowel disease

Scientific Reports ◽

10.1038/s41598-021-93671-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Rita Lippai ◽

Apor Veres-Székely ◽

Erna Sziksz ◽

Yoichiro Iwakura ◽

Domonkos Pap ◽

...

Keyword(s):

Parkinson’S Disease ◽

Inflammatory Bowel Disease ◽

Parkinson's Disease ◽

Bowel Disease ◽

Intestinal Inflammation ◽

Tnf Α ◽

Inflammatory Bowel ◽

Ht 29

AbstractRecently the role of Parkinson’s disease 7 (PARK7) was studied in gastrointestinal diseases, however, the complex role of PARK7 in the intestinal inflammation is still not completely clear. Expression and localization of PARK7 were determined in the colon biopsies of children with inflammatory bowel disease (IBD), in the colon of dextran sodium sulphate (DSS) treated mice and in HT-29 colonic epithelial cells treated with interleukin (IL)-17, hydrogen peroxide (H2O2), tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β or lipopolysaccharide (LPS). Effect of PARK7 on the synthesis of IBD related cytokines was determined using PARK7 gene silenced HT-29 cells and 3,4,5-trimethoxy-N-(4-(8-methylimidazo(1,2-a)pyridine-2-yl)phenyl)benzamide (Comp23)—compound increasing PARK7 activity—treated mice with DSS-colitis. PARK7 expression was higher in the mucosa of children with Crohn’s disease compared to that of controls. While H2O2 and IL-17 treatment increased, LPS, TNF-α or TGF-β treatment decreased the PARK7 synthesis of HT-29 cells. PARK7 gene silencing influenced the synthesis of IL1B, IL6, TNFA and TGFB1 in vitro. Comp23 treatment attenuated the ex vivo permeability of colonic sacs, the clinical symptoms, and mucosal expression of Tgfb1, Il1b, Il6 and Il10 of DSS-treated mice. Our study revealed the role of PARK7 in the regulation of IBD-related inflammation in vitro and in vivo, suggesting its importance as a future therapeutic target.

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Parkinson’s Disease: Can Targeting Inflammation Be an Effective Neuroprotective Strategy?

Frontiers in Neuroscience ◽

10.3389/fnins.2020.580311 ◽

2021 ◽

Vol 14 ◽

Author(s):

Vidar Gundersen

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Neuronal Death ◽

Brain Inflammation ◽

Dopamine Neurons ◽

Early Event ◽

Peripheral Inflammation ◽

Neuroprotective Strategy ◽

Essential Questions

The reason why dopamine neurons die in Parkinson’s disease remains largely unknown. Emerging evidence points to a role for brain inflammation in neurodegeneration. Essential questions are whether brain inflammation happens sufficiently early so that interfering with this process can be expected to slow down neuronal death and whether the contribution from inflammation is large enough so that anti-inflammatory agents can be expected to work. Here I discuss data from human PD studies indicating that brain inflammation is an early event in PD. I also discuss the role of T-lymphocytes and peripheral inflammation for neurodegeneration. I critically discuss the failure of clinical trials targeting inflammation in PD.

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