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Trashing Salmonella

Journal of Experimental Medicine
The Rockefeller University Press
Publication Date
DOI: 10.1084/jem2025iti3
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  • Medicine


2025iti IN THIS ISSUE | The Journal of Experimental Medicine 573 Text by Nicole Johnston [email protected] Fas gets protective A deadly receptor reveals a benevolent side in a study on page 575. Landau and colleagues show that the cell death–inducing receptor Fas is re- quired for protection against neurodegeneration in a mouse model of Parkinson’s disease (PD). The Fas receptor (Fas), best known for its apoptotic role in the immune system, is widely expressed in nonimmune tissues, including the central nervous system. In the brains of patients with PD, the expression of both Fas and Fas ligand (FasL) is reduced, whereas the expression of soluble Fas is elevated. Soluble Fas is a decoy receptor that impairs Fas signaling by competing for free ligand. Apoptosis has been implicated in PD neurodegeneration, but this occurs independently of caspase-8, an upstream activator in Fas-mediated apoptosis, suggesting that Fas may not be the predominant death inducer in PD. Using mice with Fas/FasL mutations, the authors showed that decreased Fas expression increased susceptibility to a PD-causing neuro- toxin. Neuronal cell loss was markedly increased in Fas-deficient mice, and these mice developed severe PD symptoms within days of toxin exposure. In contrast, two strains of mice that express Fas but have mutations in the Fas death domain, a region responsible for apop- totic signaling, were resistant to PD. Fas defects might also underlie PD in humans, as circulating T cells from patients with PD failed to up-regulate Fas expression in response to mitogenic stimulation. Although the Fas-induced signals that protect the brain have yet to be identified, these findings suggest that, in this model of PD, Fas-induced neuro- protection trumps Fas-induced cell death. Loss of dopamine-containing neurons (red) is accel- erated in the brains of Fas-deficient mice (bottom). T cell CRAC dependence Calcium transport is critical for the activation of transcri

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