{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,5,2]],"date-time":"2026-05-02T16:54:14Z","timestamp":1777740854912,"version":"3.51.4"},"posted":{"date-parts":[[2024,6,6]]},"group-title":"Neuroscience","reference-count":76,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,6,6]]},"abstract":"<jats:title>SUMMARY<\/jats:title>\n                <jats:p>\n                  Neuroinflammation is a pathological feature of many neurodegenerative diseases, including Alzheimer\u2019s disease (AD)\n                  <jats:sup>1,2<\/jats:sup>\n                  and amyotrophic lateral sclerosis (ALS)\n                  <jats:sup>3<\/jats:sup>\n                  , raising the possibility of common therapeutic targets. We previously established that cytoplasmic double-stranded RNA (cdsRNA) is spatially coincident with cytoplasmic pTDP-43 inclusions in neurons of patients with C9ORF72-mediated ALS\n                  <jats:sup>4<\/jats:sup>\n                  . CdsRNA triggers a type-I interferon (IFN-I)-based innate immune response in human neural cells, resulting in their death\n                  <jats:sup>4<\/jats:sup>\n                  . Here, we report that cdsRNA is also spatially coincident with pTDP-43 cytoplasmic inclusions in brain cells of patients with AD pathology and that type-I interferon response genes are significantly upregulated in brain regions affected by AD. We updated our machine-learning pipeline DRIAD-SP (Drug Repurposing In Alzheimer\u2019s Disease with Systems Pharmacology) to incorporate cryptic exon (CE) detection as a proxy of pTDP-43 inclusions and demonstrated that the FDA-approved JAK inhibitors baricitinib and ruxolitinib that block interferon signaling show a protective signal only in cortical brain regions expressing multiple CEs. Furthermore, the JAK family member TYK2 was a top hit in a CRISPR screen of cdsRNA-mediated death in differentiated human neural cells. The selective TYK2 inhibitor deucravacitinib, an FDA-approved drug for psoriasis, rescued toxicity elicited by cdsRNA. Finally, we identified CCL2, CXCL10, and IL-6 as candidate predictive biomarkers for cdsRNA-related neurodegenerative diseases. Together, we find parallel neuroinflammatory mechanisms between TDP-43 associated-AD and ALS and nominate TYK2 as a possible disease-modifying target of these incurable neurodegenerative diseases.\n                <\/jats:p>","DOI":"10.1101\/2024.06.04.595773","type":"posted-content","created":{"date-parts":[[2024,6,6]],"date-time":"2024-06-06T19:10:20Z","timestamp":1717701020000},"source":"Crossref","is-referenced-by-count":6,"title":["TYK2 as a novel therapeutic target in Alzheimer\u2019s Disease with TDP-43 inclusions"],"prefix":"10.64898","author":[{"given":"Laura E.","family":"K\u00f6nig","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steve","family":"Rodriguez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clemens","family":"Hug","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shayda","family":"Daneshvari","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander","family":"Chung","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gary A.","family":"Bradshaw","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Asli","family":"Sahin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"George","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robyn J.","family":"Eisert","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Federica","family":"Piccioni","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sudeshna","family":"Das","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marian","family":"Kalocsay","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Artem","family":"Sokolov","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Sorger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David E.","family":"Root","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark W.","family":"Albers","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024061012250858000_2024.06.04.595773v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2022.10.016"},{"key":"2024061012250858000_2024.06.04.595773v1.2","doi-asserted-by":"crossref","unstructured":"Hansen, D. 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