Oxidized MIF is an Alzheimer’s disease drug target relaying external risk factors to tau pathology
Year: 2025
Type: article
Abstract: During deep co-evolution of viruses and host cells, viruses have selected specific host cellular proteins redirected from physiological functions to viral needs, thereby disturbing cellular proteostasis and increasing the risk of triggering protein misfolding diseases (PMDs). Identifying virus-specific, repurposed host proteins also allows the study of fundamental cellular events in "sporadic" PMDs, independent of the virus. Here, we identify a small molecule with very strong activity against neurotropic herpes simplex virus 1 (HSV-1), modulating an allosteric site of macrophage migration inhibitory factor (MIF). The compound efficiently reduces both HSV-1-mediated and non-mediated tau phosphorylation or aggregation in vitro and in vivo. The lead compound, as well as conformation-sensitive antibodies, specifically interacts with an oxidized conformer of MIF (oxMIF) enriched in postmortem brain homogenates of patients with Alzheimer's disease (AD). OxMIF thus participates in a host-viral interface connecting HSV-1 infection, and possibly other external stressors, with tau cellular pathology characteristic for PMDs, including AD.
Source: Cell Reports Medicine
Authors: Andreas Müller-Schiffmann, Felix Torres, Anatoliy Kitaygorodskyy, Anand Ramani, Argyro Alatza, Sarah K. Tschirner, Julien Orts, Arthur Haltrich, Ingrid Prikulis, Shaofeng Yu, Debendranath Dey, Suguna Mallesh, Dharma Prasad, Dennis Solas, Verian Bader, Annemieke Rozemuller, Selina Wray, Jay Gopalakrishnan, Roland Riek, Vishwanath R. Lingappa, Carsten Korth
Institutions: Heinrich Heine University Düsseldorf, ETH Zurich, Laboratory of Physical Chemistry, Jena University Hospital, Friedrich Schiller University Jena, UCL Queen Square Institute of Neurology, University College London, University of Vienna, Amsterdam UMC Location Vrije Universiteit Amsterdam
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,620
OpenAlex ID: W4417535296