PXD043641

PXD043641 is an original dataset announced via ProteomeXchange.

Title	TYK2 inhibition reverses immune-mediated neural cell death triggered by cytoplasmic dsRNA, a damage associated molecular pattern present in Alzheimer’s Disease
Description	Neuroinflammation is a pathological feature of distinct neurodegenerative diseases, including Alzheimer’s disease (AD) and ALS, 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. CdsRNA triggers a type-I interferon-based innate immune response in human neural cells, resulting in their death. The relevance of cdsRNA in other neurodegenerative diseases remains elusive. Up to 50% of brains with Alzheimer’s Disease pathology harbor cytoplasmic pTDP-43 aggregation. Here, we report a striking pathological similarity to ALS by demonstrating that cdsRNA is spatially coincident with pTDP-43 inclusions in brain cells of patients with AD. Consistent with this finding, the analysis of AD patient RNA-seq data further showed that type-I interferon signaling is significantly increased in brain regions relevant in AD. Cytoplasmic inclusions of TDP-43 may confer nuclear hypofunction of TDP-43, which increases expression of cryptic exons in STMN2 and UNC13A. We modified our machine-learning drug repurposing predictor pipeline DRIAD (Drug Repurposing In Alzheimer’s Disease) to incorporate cryptic exon detection as a proxy of pTDP-43 inclusions. Baricitinib and ruxolitinib – FDA-approved JAK inhibitors that block interferon signaling – showed a protective signal in cryptic exon expressing brain regions but not in AD patients without cryptic exons. These results confirm that targeting JAK-mediated immune responses are not only a target in ALS but also in a cdsRNA/pTDP-43-positive subset of AD. In an in-vitro model of cdsRNA-mediated death in differentiated human neural cells lacking microglia, we conducted a CRISPR-screen. Finally, we identified CCL2, CXCL10, and IL-6 as candidate predictive CSF biomarkers for neurodegenerative diseases with an underlying dsRNA-related neuroimmune pathology. Together our findings reveal parallel mechanisms and therapeutic responses for thus far incurable neurodegenerative diseases, affording the possibility to study a therapeutic approach for more than one disease in the Neurodegenerative AD and ALS (NADALS) basket clinical trial (NCT05189106) which is an open label proof of concept clinical trial of baricitinib in patients along the Alzheimer’s and ALS disease spectrum with elevated CSF biomarkers of neuroinflammation responsive to baricitinib in model systems. Read less
HostingRepository	PRIDE
AnnounceDate	2025-12-09
AnnouncementXML	Submission_2025-12-08_19:34:38.579.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Gary Bradshaw
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2023-07-10 06:31:00	ID requested
⏵ 1	2025-12-08 19:34:39	announced

Dataset with its publication pending

submitter keyword: None

Mark Albers
contact affiliation	Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, Armenise 132, 200 Longwood Avenue, Boston, MA 02115, USA Department of Neurology, Massachusetts General Hospital, 114 16th Street, Charlestown, MA 02129, USA
contact email	albers.mark@mgh.harvard.edu
lab head
Gary Bradshaw
contact affiliation	Harvard Medical School
contact email	gary_bradshaw@hms.harvard.edu
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2025/12/PXD043641

PRIDE project URI

• PRIDE
  1. PXD043641
     1. Label: PRIDE project
     2. Name: TYK2 inhibition reverses immune-mediated neural cell death triggered by cytoplasmic dsRNA, a damage associated molecular pattern present in Alzheimer’s Disease