PXD039738

PXD039738 is an original dataset announced via ProteomeXchange.

Title	Choroid plexus targeted gene therapy for the treatment of post-hemorrhagic hydrocephalus
Description	A subset of infants and adults with hemorrhagic stroke and intraventricular hemorrhage (IVH) ultimately develop a life-threatening accumulation of cerebrospinal fluid (CSF), termed post-hemorrhagic hydrocephalus (PHH). An incomplete understanding of this variably progressive condition has hampered the development of new therapies beyond serial neurosurgical interventions. We describe an adeno-associated viral (AAV) gene augmentation approach leveraging the Na-K-Cl cotransporter, NKCC1, to enhance a choroid plexus (ChP) mechanism of CSF surveillance, potassium homeostasis, and water movement to drive decreases in ventricle size in embryonic, neonatal, and adult mouse models of IVH. Intraventricular blood led to increased CSF [K+], triggered cytosolic calcium in ChP epithelial cells, and was followed by NKCC1 activation. ChP-targeted AAV-NKCC1 rapidly reversed blood-induced ventriculomegaly and led to persistently increased CSF clearance capacity, validating the model and treating the most salient clinical features of PHH. NKCC1 is a bi-directional cotransporter, and these data demonstrate that NKCC1 activation triggered a trans-choroidal, NKCC1-dependent CSF ion/water clearance out of the ventricle. Inactive, phosphodeficient AAV-NKCC1-NT51 failed to mitigate ventriculomegaly, indicating that the beneficial effects of NKCC1 augmentation required both elevated CSF [K+] and upstream activation via phosphorylation. Excessive CSF [K+] fluctuations correlated with permanent shunting outcome in humans following hemorrhagic stroke, suggesting potential therapeutic benefits. Collectively, these data highlight a novel role for the ChP in rapid compensation for alterations in CSF homeostasis following IVH and demonstrate the utility of targeted gene therapy to mitigate intracranial fluid accumulation following hemorrhage.
HostingRepository	PRIDE
AnnounceDate	2024-05-24
AnnouncementXML	Submission_2024-05-24_01:11:38.806.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Patrick van Zalm
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2023-01-30 02:43:14	ID requested
⏵ 1	2024-05-24 01:11:39	announced

10.1016/j.neuron.2023.02.020;

Sadegh C, Xu H, Sutin J, Fatou B, Gupta S, Pragana A, Taylor M, Kalugin PN, Zawadzki ME, Alturkistani O, Shipley FB, Dani N, Fame RM, Wurie Z, Talati P, Schleicher RL, Klein EM, Zhang Y, Holtzman MJ, Moore CI, Lin PY, Patel AB, Warf BC, Kimberly WT, Steen H, Andermann ML, Lehtinen MK, Choroid plexus-targeted NKCC1 overexpression to treat post-hemorrhagic hydrocephalus. Neuron, 111(10):1591-1608.e4(2023) [pubmed]

submitter keyword: liquid chromatography, mass spectrometry,Mouse plasma proteomics

Dr. Hanno Steen
contact affiliation	Boston Childrens Hospital Harvard Medical School
contact email	hanno.steen@childrens.harvard.edu
lab head
Patrick van Zalm
contact affiliation	Boston Children's Hospital Harvard Medical School Maastricht University
contact email	patrick.vanzalm@childrens.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/2024/05/PXD039738

PRIDE project URI

• PRIDE
  1. PXD039738
     1. Label: PRIDE project
     2. Name: Choroid plexus targeted gene therapy for the treatment of post-hemorrhagic hydrocephalus