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No evidence for genetic role of the tumor necrosis factor pathway in Parkinson's disease.

ABSTRACT: Tumor necrosis factor (TNF) inhibition is under investigation as a therapeutic strategy for Parkinson's disease (PD) and REM sleep behavior disorder (RBD), yet supporting genetic evidence is limited. We used Summary-data-based Mendelian Randomization (SMR) to test whether expression level of ten TNF-related genes were causally linked to PD risk, PD progression, or RBD risk. We also analyzed associations between common and rare variants in these genes, and performed pathway specific polygenic risk score analysis, with PD. Overall, our findings do not support a genetic link between the TNF signaling and PD or RBD, arguing against this pathway as a genetically validated therapeutic target.

SUBMITTER: Shahkhali MG

PROVIDER: S-EPMC12690076 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature

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No evidence for genetic role of the tumor necrosis factor pathway in Parkinson's disease.

Ghamgosar Shahkhali Morvarid M Liu Lang L Somerville Emma N EN Noyce Alastair J AJ Gan-Or Ziv Z Senkevich Konstantin K

NPJ Parkinson's disease 20251209 1

Tumor necrosis factor (TNF) inhibition is under investigation as a therapeutic strategy for Parkinson's disease (PD) and REM sleep behavior disorder (RBD), yet supporting genetic evidence is limited. We used Summary-data-based Mendelian Randomization (SMR) to test whether expression level of ten TNF-related genes were causally linked to PD risk, PD progression, or RBD risk. We also analyzed associations between common and rare variants in these genes, and performed pathway specific polygenic ris ...[more]

PMID: 41365916

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Project description:The relevance of immune-endocrine interactions to the regulation of ovarian function in teleosts is virtually unexplored. As part of the innate immune response during infection, a number of cytokines such as tumor necrosis factor Î± (TNFÎ±) and other immune factors, are produced and act on the reproductive system. However, TNFÎ± is also an important physiological player in the ovulatory process in mammals. In the present study, we have examined for the first time the effects of TNFÎ± in vitro in preovulatory ovarian follicles of a teleost fish, the brown trout (Salmo trutta). In control and recombinant trout TNFÎ± (rtTNFÎ±)-treated granulosa cells, we examined the percentage of apoptosis by flow cytometry analysis and cell viability by propidium iodide (PI) staining. Furthermore, we determined the in vitro effects of rtTNFÎ± on follicle contraction and testosterone production in preovulatory trout ovarian follicles. In addition, we analyzed the gene expression profiles of control and rtTNFÎ±-treated ovarian tissue by microarray and real-time PCR (qPCR) analyses.Treatment with rtTNFÎ± induces ovarian cell apoptosis, decreases granulosa cell viability and stimulates the expression of genes known to be involved in the normal ovulatory process in trout. In addition, rtTNFÎ± causes a significant increase in follicle contraction and testosterone production. Also, using a salmonid-specific microarray platform (SFA2.0 immunochip) we observed that rtTNFÎ± induces the expression of genes known to be involved in inflammation, proteolysis and tissue remodeling. In view of these results, we propose that TNFÎ± could have an important role in the biomechanics of follicle weakening, ovarian rupture and oocyte expulsion during ovulation in trout, primarily through its stimulation of follicular cell apoptosis and the expression of genes involved in follicle wall proteolysis and contraction. Reproductively mature female brown trout (Salmo trutta) from a cultured stock at the Piscifactoria de BagÃ (Generalitat de Catalunya, BagÃ , Spain) were kept under natural conditions of temperature and photoperiod. Fish at the preovulatory stage (according to the position of the germinal vesicle (GV) in oocytes that were cleared using a solution previously described), were anesthesized in 3-aminobenzoic acid ethyl ester (0.1 g/l; Sigma, Alcobendas, Spain) dissolved in fresh water, and the fish were sacrificed by concussion prior to the collection of the ovaries. The dissected ovaries were immediately used for the various in vitro assays. After dissection, brown trout preovulatory ovaries were placed in HankÂ´s balanced salt solution (HBSS) and individual ovarian follicles were manually separated with forceps from each ovary on ice, as previously described. To collect ovarian tissue for RNA extraction, preovulatory follicles from each of a total of three females were incubated (400 follicles/50 ml) in HBSS-BSA in the absence or presence of rtTNFÎ± (100 ng/ ml, dissolved directly in HBSS-BSA), at 15ÂºC for 24 h with gentle shaking (100 rpm). At the end of the incubation follicles (previously de-yolked by gentle pressure) were removed, flash frozen in liquid nitrogen and stored at -80ÂºC until assayed.

Dataset Information

No evidence for genetic role of the tumor necrosis factor pathway in Parkinson's disease.

Publications

No evidence for genetic role of the tumor necrosis factor pathway in Parkinson's disease.

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