TYK2 mediates neuroinflammation in Alzheimer’s disease brains with TDP-43 pathology
Neuroinflammation is a pathological feature of neurodegenerative diseases like Alzheimer's disease and ALS. Cytoplasmic dsRNA (cdsRNA) triggers a type-I interferon response in human neural cells, leading to their death, and is found in neurons of C9ORF72-ALS patients. Here, we report the spatial coincidence of cdsRNA and pTDP-43 inclusions in human postmortem tissue with Alzheimer's disease pathology, and upregulated interferon response genes in affected regions. CdsRNA also accumulates in a human TDP-43 G298S iPSC cortical neuronal model. We use cryptic exon detection as a proxy for TDP-43 mislocalization and demonstrate that FDA-approved JAK inhibitors baricitinib and ruxolitinib, which block interferon signaling, show protective effects only in brains with elevated cryptic exon expression. A CRISPR screen reveals TYK2 as a top hit, and TYK2 knockdown and the selective TYK2 inhibitor deucravacitinib rescue cdsRNA-induced toxicity. We find parallel neuroinflammatory mechanisms, dependent on TYK2 - a potential disease-modifying target - for TDP-43-associated Alzheimer's disease and C9ORF72-ALS.
Authors
- Federica Piccioni (ORCID: https://orcid.org/0000-0003-1210-3210)
- Ioanna Tzoulaki (ORCID: https://orcid.org/0000-0002-4275-9328)
- Gary A. Bradshaw (ORCID: https://orcid.org/0000-0001-9724-6100)
- Mark W. Albers (ORCID: https://orcid.org/0000-0001-7855-3455)
- Robyn J. Eisert (ORCID: https://orcid.org/0000-0001-7977-249X)
- Peter Karl Sorger (ORCID: https://orcid.org/0000-0002-3364-1838)
- Christine Marques
- Artem Sokolov (ORCID: https://orcid.org/0000-0002-8056-0504)
- Abbas Dehghan (ORCID: https://orcid.org/0000-0001-6403-016X)
- George Zhou (ORCID: https://orcid.org/0000-0002-1345-2634)
- Marian Kalocsay (ORCID: https://orcid.org/0000-0002-4187-5829)
- David E. Root (ORCID: https://orcid.org/0000-0001-5122-861X)
- Brian J. Wainger (ORCID: https://orcid.org/0000-0002-3664-7231)
- Aslı Şahin (ORCID: https://orcid.org/0000-0002-4706-3071)
- Shayda Daneshvari
- Max Tsai
- Sharon Powley
- James Yarmolinsky
- Mark Appleman
- Sudeshna Das
- Laura E. König
- Alexander Chung
- Clemens Hug
- Yuyu Song
- Steve Rodriguez
Institutions
- Broad Institute (US)
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- The University of Texas MD Anderson Cancer Center (US)
- Harvard University (US)
- Academy of Athens (GR)
- Massachusetts General Hospital (US)
- UK Dementia Research Institute (GB)
- Etiometry (United States) (US)
- Center for Systems Biology (US)
- Imperial College London (GB)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-03-14
- DOI
- https://doi.org/10.1038/s41467-026-70243-3
- Primary Topic
- RNA regulation and disease
- Type
- article
- Field-Weighted Citation Impact
- 0.00