PXD057067

PXD057067 is an original dataset announced via ProteomeXchange.

Title	Telmisartan is neuroprotective in a hiPSC-derived spinal microtissue model for C9orf72-ALS via inhibition of neuroinflammation
Description	Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by motor neurons (MN) loss. Mutations in C9orf72 are the leading genetic cause of ALS and involve hexanucleotide repeat expansions (HRE) in the noncoding region of the gene. Neuroinflammation is a key feature and candidate therapeutic target in ALS, particularly in individuals with C9orf72 mutations (C9-ALS), as the gene affects microglial cell function and neuroinflammation. Here, we established a novel protocol to model the ALS neuroinflammatory axis by combining C9-ALS human iPSC-derived spinal MNs, astrocytes, and microglia. The resulting three-dimensional (3D) Spinal Microtissue (SM) represents a scalable multicellular platform for disease modeling and drug discovery. We next performed a screen of 190 FDA-approved compounds in C9-ALS SMs and in microglia-only tissues. Sartans, a class of Angiotensin II Receptor I Blockers (ARB), were identified as top hits in reducing C9-ALS-related neuroinflammation, including IL-6 and IL-8 levels in the culture supernatant. We validated these findings in SMs from two additional C9-ALS hiPSC lines and in isogenic control cultures using telmisartan, a particularly potent and brain penetrant sartan. Further, telmisartan rescued C9-ALS related MN death in both coculture and tricultures conditions and restored MN cell proportions within C9-ALS SMs. Our study suggests that C9-ALS microglia are toxic to MNs, and that telmisartan can attenuate microglia-related neuroinflammation and MN death presenting a potential treatment for C9-ALS.
HostingRepository	PRIDE
AnnounceDate	2025-07-28
AnnouncementXML	Submission_2025-07-27_16:11:07.527.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Zhuoning Li
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2024-10-22 13:12:47	ID requested
⏵ 1	2025-07-27 16:11:08	announced

Sonustun B, Vahsen BF, Ledesma-Terr, ó, n M, Li Z, Tuffery L, Xu N, Calder EL, Jungverdorben J, Weber L, Zhong A, Miguez DG, Monetti M, Zhou T, Giacomelli E, Studer L, Telmisartan is neuroprotective in a hiPSC-derived spinal microtissue model for C9orf72 ALS via inhibition of neuroinflammation. Stem Cell Reports, 20(7):102535(2025) [pubmed]

10.1016/j.stemcr.2025.102535;

submitter keyword: neuroinflammation

neurodegeneration

Amyotrophic Lateral Sclerosis

C9ORF72

human pluripotent stem cells

cellular interactions

motor neurons

astrocytes

microglia

spinal cord

triculture

three-dimension

microtissue

drug screen

sartans

telmisartan

Lorenz Studer
contact affiliation	Developmental Biology Program & Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
contact email	studerl@mskcc.org
lab head
Zhuoning Li
contact affiliation	MSKCC
contact email	liz2@mskcc.org
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/2025/07/PXD057067

PRIDE project URI

• PRIDE
  1. PXD057067
     1. Label: PRIDE project
     2. Name: Telmisartan is neuroprotective in a hiPSC-derived spinal microtissue model for C9orf72-ALS via inhibition of neuroinflammation