Biology subjects

Oertel, W.

Publications and source records attributed to Oertel, W..

3 recordsLinked to original sources

bioRxiv2024

Integrated multi-omics highlights alterations of gut microbiome functions in prodromal and idiopathic Parkinson's disease

Parkinsons disease (PD) is associated with gut microbiome shifts, but the functional consequences remain unclear. Here, we use an integrated multi-omics approach to compare the gut microbiomes of individuals with PD and prodromal PD as well as healthy individuals. After analyzing each omics, meta-metabolomic was selected to inform the analysis as it represents the most discriminatory and robust ome. We identified 11 metabolites that were differentially abundant between the groups, amongst which {beta}-glutamate was increased in PD and prodromal PD, and correlated with the transcriptional activities of Methanobrevibacter smithii and Clostridium spp. We identified decreases in transcripts, but not in gene abundances, related to glutamate metabolism, bile acids, chemotaxis and flagellar assembly in PD, particularly in keystone genera such as Roseburia, Agathobacter and Blautia. Our findings, integrated into the Expobiome map, reveal multifactorial microbiome alterations which converge with PD pathways. Our study highlights the importance of investigating the gut microbiomes functional dimensions to better resolve microbiome-host interactions in health and disease.

systems biology↗

bioRxiv2020

JN403, an alpha-7-nicotine-acetylcholine-receptor agonist, reduces alpha-synuclein induced inflammatory parameters of in vitro microglia but fails to attenuate the reduction of TH positive nigral neurons in a focal alpha-synuclein overexpression mouse model of Parkinson's disease.

Alpha-7-nicotine-acetylcholine-receptor (7-nAChRs) agonists modulate the cholinergic antiinflammatory pathway to attenuate proinflammatory signals and reduce dopaminergic neuronal cell loss in toxin-induced experimental murine models of Parkinsons disease (PD). The protein -synuclein (Syn) is considered to represent the major pathogenic component in the etiology and progression of sporadic PD. However, no research has been performed to evaluate the effect of 7-nAChR agonists in human Syn mediated models of PD. We, therefore, investigated the effect of the compound JN403, an 7-nAChR specific agonist, in Syn treated in vitro microglia culture and in a human Syn overexpression in vivo mouse model. In primary mouse microglia cells, Syn fragment 61-140 treatment increased the release of nitric oxide (NO), tumor necrosis factor (TNF)- and interleukin (IL)-6, and decreased cell viability. In contrast, 100 nM or 1 M of JN403 co-incubation significantly reduced the level of NO and TNF- release in the microglial cells. For in-vivo testing of JN403, a recombinant adeno-associated viral vector (rAAV)-mediated unilateral intranigral overexpression of human wild-type-Syn (WT-Syn) or of the control protein luciferase (luc) was induced via stereotactic delivery in C57/BL6N mice. Targeted WT-Syn overexpression reduced 20% of the number of tyrosine hydroxylase (TH) positive (+) nigral neurons after 10 weeks. Subcutaneous daily treatment of 30 mg/kg JN403 over 9 weeks starting at postoperative week 1 did not alter the decrease of TH+ neuronal numbers, and microglial density in WT-Syn overexpression mouse model. The reduced density of TH+ striatal terminals in the WT-Syn groups was also not recovered by the JN403 treatment. In summary, JN403, an 7-nAChR specific agonist shows a beneficial effect on ameliorating proinflammatory signals in Syn exposed microglia cells. However, no significant in-vivo treatment effect was found in an intranigral WT-Syn overexpression mouse model of PD.

neuroscience↗

bioRxiv2019

Fine-mapping of SNCA in REM sleep behavior disorder and overt synucleinopathies

ObjectiveREM-sleep behavior disorder (RBD) is a prodromal synucleinopathy, as >80% will eventually convert to overt synucleinopathy. We performed an in-depth analysis of the SNCA locus to identify RBD-specific risk variants.\n\nMethodsFull sequencing and genotyping of SNCA was performed in isolated/idiopathic RBD (iRBD, n=1,076), Parkinsons disease (PD, n=1,013), and dementia with Lewy bodies (DLB, n=415), and in control subjects (n=6,155). A replication cohort from 23andMe of PD patients with probable RBD (pRBD) was also analyzed (cases n=1,782, controls n=131,250). Adjusted logistic regression models and meta-analyses were performed. Effects on conversion rate were analyzed in 432 RBD patients with available data using Kaplan-Meier survival analysis.\n\nResultsA 5-region SNCA variant (rs10005233) was associated with iRBD (OR=1.43, p=1.1E-08), which was replicated in pRBD. This variant is in linkage disequilibrium (LD) with other 5 risk variants across the different synucleinopathies. An independent iRBD-specific suggestive association (rs11732740) was detected at the 3 of SNCA (OR=1.32, p=4.7E-04, not statistically significant after Bonferroni correction). Homozygous carriers of both iRBD-specific SNPs were at highly increased risk for iRBD (OR=5.74, p=2E-06). The known top PD-associated variant (3 variant rs356182) had an opposite direction of effect in iRBD compared to PD.\n\nInterpretationThere is a distinct pattern of association at the SNCA locus in RBD as compared to PD, with an opposite direction of effect at the 3 of SNCA. Several 5 SNCA variants are associated with iRBD and with pRBD in overt synucleinopathies, and may suggest a cognitive component to this region.

genetics↗