TY - JOUR
T1 - Oxidized MIF is an Alzheimer’s disease drug target relaying external risk factors to tau pathology
AU - Müller-Schiffmann, Andreas
AU - Torres, Felix
AU - Kitaygorodskyy, Anatoliy
AU - Ramani, Anand
AU - Alatza, Argyro
AU - Tschirner, Sarah K.
AU - Orts, Julien
AU - Haltrich, Arthur
AU - Prikulis, Ingrid
AU - Yu, Shaofeng
AU - Dey, Debendranath
AU - Mallesh, Suguna
AU - Prasad, Dharma
AU - Solas, Dennis
AU - Bader, Verian
AU - Rozemuller, Annemieke
AU - Wray, Selina
AU - Gopalakrishnan, Jay
AU - Riek, Roland
AU - Lingappa, Vishwanath R.
AU - Korth, Carsten
N1 - Publisher Copyright:
© 2025 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license. http://creativecommons.org/licenses/by/4.0/
PY - 2026/1/20
Y1 - 2026/1/20
N2 - SummaryDuring 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.
AB - SummaryDuring 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.
KW - Alzheimer’s disease
KW - herpes virus
KW - macrophage migration inhibitory factor
KW - neurodegeneration
KW - oxMIF
KW - protein aggregation
KW - proteostasis
KW - risk factor
KW - tau
KW - tauopathy
UR - https://www.scopus.com/pages/publications/105028283440
U2 - 10.1016/j.xcrm.2025.102520
DO - 10.1016/j.xcrm.2025.102520
M3 - Article
C2 - 41418773
SN - 2666-3791
VL - 7
JO - Cell Rep. Med.
JF - Cell Rep. Med.
IS - 1
M1 - 102520
ER -