Choroid plexus-targeted NKCC1 overexpression to treat post-hemorrhagic hydrocephalus

Sadegh, Cameron; Xu, Huixin; Sutin, Jason; Fatou, Benoit; Gupta, Sumiti; Pragana, Aja; Taylor, Milo; Kalugin, Peter N.; Zawadzki, Miriam E.; Alturkistani, Osama; Shipley, Frederick B.; Dani, Neil; Fame, Ryann M.; Wurie, Zainab; Talati, Pratik; Schleicher, Riana; Klein, Eric M.; Zhang, Yong; Holtzman, Michael J.; Moore, Christopher I.; Lin, Pei-Yi; Warf, Benjamin C.; Kimberly, W. Taylor; Steen, Hanno; Andermann, Mark L.; Lehtinen, Maria K.

doi:10.1016/j.neuron.2023.02.020

Cited by 25 publications

(30 citation statements)

References 85 publications

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“…The latter can be therefore considered an estimation of the maximum amount of water molecules transported per alternating access cycle. Interestingly, these semiquantitative observation enrich the current experimental evidence for water transport by NKCC1 , and its functional implications in the context of CSF accumulation recently demonstrated. , Indeed, water may cross the membrane via the formation of permeable states, as has been reported for a wide range of transporters, including Na + /glucose transporter (SGLT), glutamate transporter (Glt ph ), glycerol-3-phosphate transporter (GlpT), sodium-benzylhydantoin transporter (Mhp1), and the maltose transporter, and more recently also shown for the sodium/proton antiporter PaNhaP …”

Section: Discussionsupporting

confidence: 76%

“…Interestingly, these semiquantitative observation enrich the current experimental evidence for water transport by NKCC1 31,32 and its functional implications in the context of CSF accumulation recently demonstrated. 33,34 Indeed, water may cross the membrane via the formation of permeable states, as has been reported for a wide range of transporters, including Na + /glucose transporter (SGLT), glutamate transporter (Glt ph ), glycerol-3-phosphate transporter (GlpT), sodium-benzylhydantoin transporter (Mhp1), and the maltose transporter, 35 and more recently also shown for the sodium/proton antiporter PaNhaP. 36 One more mechanistic feature from our simulations is the interhelical interface intrinsically associated with NKCC1's transport capabilities.…”

Section: ■ Discussionmentioning

confidence: 99%

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Cation Chloride Cotransporter NKCC1 Operates through a Rocking-Bundle Mechanism

Ruiz Munevar,

Rizzi,

Portioli

et al. 2023

J. Am. Chem. Soc.

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

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Section: Discussionsupporting

confidence: 76%

Section: ■ Discussionmentioning

confidence: 99%

Cation Chloride Cotransporter NKCC1 Operates through a Rocking-Bundle Mechanism

Ruiz Munevar,

Rizzi,

Portioli

et al. 2023

J. Am. Chem. Soc.

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“…Activation of microglial nucleotide-binding and oligomerization domain-like receptors can be triggered by inflammation-induced tissue damage of CNS barrier epithelia (the CP epithelia and ependyma) and associated damage-associated molecular pattern molecule release, which could propagate and sustain the neuroinflammatory reaction in the CP 28,29 . In addition, the bidirectional Na-K-Cl cotransporter (ie, NKCC1) plays a key role in CP to mitigate hydrocephalus, but bumetanide, a NKCC1 inhibitor, and its derivatives show a low level of CNS penetration indicating that it might not always be effective 27,30,31 . Therefore, Karimy et al 5 proposed that targeting inflammation as opposed to CP epithelia ion transport is a particularly promising therapeutic approach for hydrocephalus; that is, beyond driving the initial CSF hypersecretory response, inflammation is likely to contribute to the ensuing tissue damage and release of damage-associated molecular pattern that ultimately leads to sustained hydrocephalus.…”

Section: Discussionmentioning

confidence: 99%

“…28,29 In addition, the bidirectional Na-K-Cl cotransporter (ie, NKCC1) plays a key role in CP to mitigate hydrocephalus, but bumetanide, a NKCC1 inhibitor, and its derivatives show a low level of CNS penetration indicating that it might not always be effective. 27,30,31 Therefore, Karimy et al 5 proposed that targeting inflammation as opposed to CP epithelia ion transport is a particularly promising therapeutic approach for hydrocephalus; that is, beyond driving the initial CSF hypersecretory response, inflammation is likely to contribute to the ensuing tissue damage and release of damage-associated molecular pattern that ultimately leads to sustained hydrocephalus.…”

Section: Discussionmentioning

confidence: 99%

DPA714 PET Imaging Shows That Inflammation of the Choroid Plexus Is Active in Chronic-Phase Intracerebral Hemorrhage

Yao,

Gao,

Fang

et al. 2023

Clin Nucl Med

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Purpose Our aims were to investigate the presence of choroid plexus (CP) inflammation in chronic-phase intracerebral hemorrhage (ICH) patients and to characterize any inflammatory cells in the CP. Patients and Methods An in vivo 18F-DPA714 PET study was undertaken in 22 chronic-phase ICH patients who were admitted to the First Affiliated Hospital of Fujian Medical University or Tianjin Medical University General Hospital from April 2017 to June 2020. Ten control participants with nonhemorrhagic central nervous system diseases were included. Choroid plexus 18F-DPA714 uptake was calculated as the average SUVR. To aid the interpretation of the 18F-DPA714 uptake results at the CP level, Cy5-DPA714 in vivo imaging and immunofluorescence staining were used to show the presence of CP inflammation in an ICH mouse model during the chronic phase (14 weeks after ICH). Then immunofluorescence staining against translocator protein and other specific biomarkers was used to characterize the cells present in the inflamed CP of ICH mice in the chronic phase. Results PET imaging showed that CP DPA714 SUVRs in chronic-phase ICH patients were higher than in controls (mean CP SUVR ± SD; ICH group: 1.05 ± 0.35; control group: 0.81 ± 0.21; P = 0.006). Immunofluorescence staining of the CP in ICH model mice identified a population of CD45+ immune cells, peripheral monocyte-derived CD14+ cells, CD68+ phagocytes, and CD11b+ resident microglia/macrophages expressing translocator protein, possibly contributing to the increased 18F-DPA714 uptake. Conclusions Our study shows that CP DPA714 uptake in chronic-phase ICH patients was higher than that of participants with nonhemorrhagic central nervous system diseases, which means that CP inflammation is still active in chronic-phase ICH patients.

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“…Developing specific genetic tools to manipulate the ChP in a time-specific manner is a game changer. It has been so far very difficult to specifically target the ChP using genetics, and often researchers have made use of the AAV2/5 serotype which preferentially target the ChP epithelial cells in rodents (Chen et al , 2020; Haddad et al , 2013; Jang & Lehtinen, 2022; Sadegh et al , 2023; Xu et al , 2021). Here we generated a versatile genetic tool using the Gal4-UAS system allowing for the first time to specifically investigate and manipulate the ChP epithelial cells in the zebrafish.…”

Section: Discussionmentioning

confidence: 99%

The evolutionary conserved choroid plexus sustains the homeostasis of brain ventricles in zebrafish

Jeong,

Andreassen,

Hoang

et al. 2023

Preprint

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SummaryThe choroid plexus produces cerebrospinal fluid (CSF) by transport of electrolytes and water from the vasculature to the brain ventricles. The choroid plexus plays additional roles in brain development and homeostasis by secreting neurotrophic molecules, and by serving as a CSF-blood barrier and immune interface. Prior studies have identified transporters on the epithelial cells that transport water and ions into the ventricles and tight junctions involved in the CSF-blood barrier. Yet, how the choroid plexus epithelial cells maintain the brain ventricle system and control brain physiology remain unresolved. To provide novel insights into the physiological roles of the choroid plexus, we use juvenile and adult zebrafish as model systems. Upon histological and transcriptomic analyses, we first identified that the zebrafish choroid plexus is highly conserved with the mammalian choroid plexus and that it expresses all transporters necessary for CSF secretion. Using novel genetic lines, we also identified that the choroid plexus secretes proteins into the CSF. Next, we generated a transgenic line allowing us to ablate specifically the epithelial cells in the choroid plexus. Using the ablation system, we identified a reduction of the ventricular sizes, but no alterations of the CSF-blood barrier. Altogether, our findings identified that the zebrafish choroid plexus is evolutionarily conserved and critical for maintaining the size and homeostasis of the brain ventricles.Graphical abstractHighlightsThe zebrafish choroid plexus has similar anatomical features with the mammalian choroid plexus.The expression of choroid plexus transporters involved in CSF secretion is evolutionarily conserved across vertebrates.Generation of a novel choroid plexus specific driver line shows that the choroid plexus epithelial cells secrete proteins into CSF.Ablation of the choroid plexus decreases the size of the brain ventricles.

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Choroid plexus-targeted NKCC1 overexpression to treat post-hemorrhagic hydrocephalus

Cited by 25 publications

References 85 publications

Cation Chloride Cotransporter NKCC1 Operates through a Rocking-Bundle Mechanism

Cation Chloride Cotransporter NKCC1 Operates through a Rocking-Bundle Mechanism

DPA714 PET Imaging Shows That Inflammation of the Choroid Plexus Is Active in Chronic-Phase Intracerebral Hemorrhage

The evolutionary conserved choroid plexus sustains the homeostasis of brain ventricles in zebrafish

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