Cation Chloride Cotransporter NKCC1 Operates through a Rocking-Bundle Mechanism DOI Creative Commons
Manuel José Ruiz Munevar, Valerio Rizzi, Corinne Portioli

et al.

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 146(1), P. 552 - 566

Published: Dec. 26, 2023

The sodium, potassium, and chloride cotransporter 1 (NKCC1) plays a key role in tightly regulating ion shuttling across cell membranes. Lately, its aberrant expression function have been linked to numerous neurological disorders cancers, making it novel highly promising pharmacological target for therapeutic interventions. A better understanding of how NKCC1 dynamically operates would therefore broad implications ongoing efforts toward exploitation as through modulation. Based on recent structural data NKCC1, we reveal conformational motions that are function. Using extensive deep-learning-guided atomistic simulations models embedded into the membrane, captured complex dynamical transitions between alternate open conformations inner outer vestibules demonstrated has water-permeable states. We found these previously undefined occur via rocking-bundle mechanism characterized by cooperative angular motion transmembrane helices (TM) 4 9, with contribution extracellular tip TM 10. be critical modulating transportation NKCC1's water transporting capabilities. Specifically, identified interhelical contacts 10 6, which functionally validated mutagenesis experiments new targeted mutants. conclude showing those residues conserved most Na+-dependent cation cotransporters (CCCs), highlights their mechanistic implications, opening way strategies modulation thus potential drug action selected CCCs.

Language: Английский

The choroid plexus synergizes with immune cells during neuroinflammation DOI Creative Commons
Huixin Xu, Peter Lotfy, Sivan Gelb

et al.

Cell, Journal Year: 2024, Volume and Issue: 187(18), P. 4946 - 4963.e17

Published: July 31, 2024

Language: Английский

Citations

22
Multiphoton fluorescence microscopy for in vivo imaging DOI
Chris Xu, Maiken Nedergaard, Deborah J. Fowell

et al.

Cell, Journal Year: 2024, Volume and Issue: 187(17), P. 4458 - 4487

Published: Aug. 1, 2024

Language: Английский

Citations

21
The evolutionarily conserved choroid plexus contributes to the homeostasis of brain ventricles in zebrafish DOI Creative Commons
Inyoung Jeong,

Søren Norge Andreassen,

Linh Hoang

et al.

Cell Reports, Journal Year: 2024, Volume and Issue: 43(6), P. 114331 - 114331

Published: June 1, 2024

The choroid plexus (ChP) produces cerebrospinal fluid (CSF). It also contributes to brain development and serves as the CSF-blood barrier. Prior studies have identified transporters on epithelial cells that transport water ions from blood vasculature ventricles tight junctions involved in Yet, how ChP control physiology remains unresolved. We use zebrafish provide insights into physiological roles of ChP. Upon histological transcriptomic analyses, we identify is conserved with mammals expresses CSF secretion. Next, show secrete proteins CSF. By ablating cells, a reduction ventricular sizes without alterations Altogether, our findings reveal size homeostasis ventricles.

Language: Английский

Citations

10
Choroid plexus mast cells drive tumor-associated hydrocephalus DOI Creative Commons

Yiye Li,

Can Di,

Shi‐Jian Song

et al.

Cell, Journal Year: 2023, Volume and Issue: 186(26), P. 5719 - 5738.e28

Published: Dec. 1, 2023

Language: Английский

Citations

19
Mechanisms of cerebrospinal fluid and brain interstitial fluid production DOI Creative Commons
Jianming Xiang, Ya Hua, Guohua Xi

et al.

Neurobiology of Disease, Journal Year: 2023, Volume and Issue: 183, P. 106159 - 106159

Published: May 19, 2023

Fluid homeostasis is fundamental for brain function with cerebral edema and hydrocephalus both being major neurological conditions. movement from blood into one crucial element in fluid homeostasis. Traditionally it has been thought to occur primarily at the choroid plexus (CP) as cerebrospinal (CSF) secretion due polarized distribution of ion transporters CP epithelium. However, there are currently controversies importance secretion, just how transport occurs that epithelium versus other sites, well direction flow ventricles. The purpose this review evaluate evidence on CSF vasculature differs tissues, e.g., blood-brain barrier may drive flow. It also addresses recent promising data two potential targets modulating Na

Language: Английский

Citations

18
The choroid plexus maintains adult brain ventricles and subventricular zone neuroblast pool, which facilitates poststroke neurogenesis DOI Creative Commons

Александр Таранов,

Alicia Bedolla, Eri Iwasawa

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(28)

Published: July 2, 2024

The brain’s neuroreparative capacity after injuries such as ischemic stroke is partly contained in the neurogenic niches, primarily subventricular zone (SVZ), which lies close contact with cerebrospinal fluid (CSF) produced by choroid plexus (ChP). Despite wide range of their proposed functions, ChP/CSF remain among most understudied compartments central nervous system (CNS). Here, we report a mouse genetic tool (the ROSA26iDTR line) for noninvasive, specific, and temporally controllable ablation CSF-producing ChP epithelial cells to assess roles CSF brain homeostasis injury. Using this model, demonstrate that causes rapid permanent volume loss both aged young adult brains, accompanied disruption ependymal cilia bundles. Surprisingly, did not result overt neurological deficits at 1 mo postablation. However, observed pronounced decrease pool SVZ neuroblasts (NBs) following ablation, occurs due enhanced migration into olfactory bulb. In middle cerebral artery occlusion model stroke, NB lesion site was also reduced CSF-depleted mice. Thus, our study establishes an important role regulating regenerative under normal conditions stroke.

Language: Английский

Citations

7
Dual function of the choroid plexus: Cerebrospinal fluid production and control of brain ion homeostasis DOI Creative Commons
Nanna MacAulay, Trine L. Toft‐Bertelsen

Cell Calcium, Journal Year: 2023, Volume and Issue: 116, P. 102797 - 102797

Published: Sept. 15, 2023

The choroid plexus is a small monolayered epithelium located in the brain ventricles and serves to secrete cerebrospinal fluid (CSF) that envelops fills central ventricles. CSF secretion sustained with concerted effort of range membrane transporters polarized fashion this tissue. Prominent amongst these are Na

Language: Английский

Citations

15
Iron homeostasis and post-hemorrhagic hydrocephalus: a review DOI Creative Commons
Shelei Pan, Andrew T. Hale, Mackenzie Lemieux

et al.

Frontiers in Neurology, Journal Year: 2024, Volume and Issue: 14

Published: Jan. 12, 2024

Iron physiology is regulated by a complex interplay of extracellular transport systems, coordinated transcriptional responses, and iron efflux mechanisms. Dysregulation metabolism can result in defects myelination, neurotransmitter synthesis, neuronal maturation. In neonates, germinal matrix-intraventricular hemorrhage (GMH-IVH) causes overload as blood breakdown the ventricles brain parenchyma which lead to post-hemorrhagic hydrocephalus (PHH). However, precise mechanisms GMH-IVH results PHH remain elusive. Understanding molecular determinants homeostasis developing may improved therapies. This manuscript reviews various roles has development, characterizes our understanding brain, describes potential cause injury. We also review novel preclinical treatments for IVH that specifically target iron. handling within central nervous system provide basis preventative, targeted iron-mediated pathogenesis PHH.

Language: Английский

Citations

4
Transporters, Ion Channels, and Junctional Proteins in Choroid Plexus Epithelial Cells DOI Creative Commons
Masaki Ueno, Yoichi Chiba, Ryuta Murakami

et al.

Biomedicines, Journal Year: 2024, Volume and Issue: 12(4), P. 708 - 708

Published: March 22, 2024

The choroid plexus (CP) plays significant roles in secreting cerebrospinal fluid (CSF) and forming circadian rhythms. A monolayer of epithelial cells with tight adherens junctions CP forms the blood–CSF barrier to control movement substances between blood ventricles, as microvessels stroma have fenestrations endothelial cells. are equipped several kinds transporters ion channels transport nutrient secrete CSF. In addition, junctional components also contribute CSF production well formation. However, it remains unclear how pathogenesis neurodegenerative disorders. this manuscript, recent findings regarding distribution significance transporters, channels, proteins introduced, changes expression their pathophysiology brain disorders reviewed.

Language: Английский

Citations

4
Genetic and molecular mechanisms of hydrocephalus DOI Creative Commons

Xuehai Deng,

Yung‐Yi Chen, Qing Duan

et al.

Frontiers in Molecular Neuroscience, Journal Year: 2025, Volume and Issue: 17

Published: Jan. 7, 2025

Hydrocephalus is a neurological condition caused by aberrant circulation and/or obstructed cerebrospinal fluid (CSF) flow after cerebral ventricle abnormal dilatation. In the past 50 years, diagnosis and treatment of hydrocephalus have remained understudied underreported, little progress has been made with respect to prevention or treatment. Further research on pathogenesis essential for developing new diagnostic, preventive, therapeutic strategies. Various genetic molecular abnormalities contribute mechanisms hydrocephalus, including gene deletions mutations, activation cellular inflammatory signaling pathways, alterations in water channel proteins, disruptions iron metabolism. Several studies demonstrated that modulating expression key TGF-β, VEGF, Wnt, AQP, NF-κB, NKCC, can significantly influence onset progression hydrocephalus. This review summarizes discusses may be involved at both levels. While obstructive often addressed removing obstruction, most cases require strategies involve merely slowing disease correcting CSF patterns. There few breakthroughs

Language: Английский

Citations

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