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https://www.readbyqxmd.com/read/29772390/pathobiology-of-christianson-syndrome-linking-disrupted-endosomal-lysosomal-function-with-intellectual-disability-and-sensory-impairments
#1
Mallory Kerner-Rossi, Maria Gulinello, Steven Walkley, Kostantin Dobrenis
Christianson syndrome (CS) is a recently described rare neurogenetic disorder presenting early in life with a broad range of neurological symptoms, including severe intellectual disability with nonverbal status, hyperactivity, epilepsy, and progressive ataxia due to cerebellar atrophy. CS is due to loss-of-function mutations in SLC9A6, encoding NHE6, a sodium-hydrogen exchanger involved in the regulation of early endosomal pH. Here we review what is currently known about the neuropathogenesis of CS, based on insights from experimental models, which to date have focused on mechanisms that affect the CNS, specifically the brain...
May 14, 2018: Neurobiology of Learning and Memory
https://www.readbyqxmd.com/read/29567836/histone-deacetylase-mediated-regulation-of-endolysosomal-ph
#2
Hari Prasad, Rajini Rao
The pH of the endolysosomal system is tightly regulated by a balance of proton pump and leak mechanisms that are critical for storage, recycling, turnover, and signaling functions in the cell. Dysregulation of endolysosomal pH has been linked to aging, amyloidogenesis, synaptic dysfunction, and various neurodegenerative disorders, including Alzheimer's disease. Therefore, understanding the mechanisms that regulate luminal pH may be key to identifying new targets for managing these disorders. Metaanalysis of yeast microarray databases revealed that nutrient limiting conditions inhibited the histone deacetylase (HDAC) Rpd3 and thereby upregulated transcription of the endosomal Na+ /H+ exchanger Nhx1, resulting in vacuolar alkalinization...
March 22, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29351414/the-murine-choroid-plexus-epithelium-expresses-the-2cl-h-exchanger-clc-7-and-na-h-exchanger-nhe6-in-the-luminal-membrane-domain
#3
Helle H Damkier, Henriette L Christensen, Inga B Christensen, Qi Wu, Robert A Fenton, Jeppe Praetorius
The choroid plexus epithelium within the brain ventricles secretes the majority of the cerebrospinal fluid (CSF). The luminal Na+ -K+ -ATPase acts in concert with a host of other transport proteins to mediate efficient fluid secretion across the epithelium. The CSF contains little protein buffer, but the pH value seems nonetheless maintained within narrow limits, even when faced with acid-base challenges. The involvement of choroid plexus acid-base transporters in CSF pH regulation is highlighted by the expression of several acid-base transporters in the epithelium...
April 1, 2018: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/29349289/mixed-neurodevelopmental-and-neurodegenerative-pathology-in-nhe6-null-mouse-model-of-christianson-syndrome
#4
Meiyu Xu, Qing Ouyang, Jingyi Gong, Matthew F Pescosolido, Brandon S Pruett, Sasmita Mishra, Michael Schmidt, Richard N Jones, Ece D Gamsiz Uzun, Sofia B Lizarraga, Eric M Morrow
Christianson syndrome (CS) is an X-linked disorder resulting from loss-of-function mutations in SLC9A6 , which encodes the endosomal Na+ /H+ exchanger 6 (NHE6). Symptoms include early developmental delay, seizures, intellectual disability, nonverbal status, autistic features, postnatal microcephaly, and progressive ataxia. Neuronal development is impaired in CS, involving defects in neuronal arborization and synaptogenesis, likely underlying diminished brain growth postnatally. In addition to neurodevelopmental defects, some reports have supported neurodegenerative pathology in CS with age...
November 2017: ENeuro
https://www.readbyqxmd.com/read/29212874/the-na-k-h-exchanger-nhx1-controls-multivesicular-body-vacuolar-lysosome-fusion
#5
Mahmoud Abdul Karim, Christopher Leonard Brett
Loss-of-function mutations in human endosomal Na+ (K+ )/H+ exchangers (NHEs) NHE6 and NHE9 are implicated in neurological disorders including Christianson syndrome, autism, and attention deficit and hyperactivity disorder. These mutations disrupt retention of surface receptors within neurons and glial cells by affecting their delivery to lysosomes for degradation. However, the molecular basis of how these endosomal NHEs control endocytic trafficking is unclear. Using Saccharomyces cerevisiae as a model, we conducted cell-free organelle fusion assays to show that transport activity of the orthologous endosomal NHE Nhx1 is important for multivesicular body (MVB)-vacuolar lysosome fusion, the last step of endocytosis required for surface protein degradation...
February 1, 2018: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28635961/hypoxia-induced-mobilization-of-nhe6-to-the-plasma-membrane-triggers-endosome-hyperacidification-and-chemoresistance
#6
Fabrice Lucien, Pierre-Paul Pelletier, Roxane R Lavoie, Jean-Michel Lacroix, Sébastien Roy, Jean-Luc Parent, Dominique Arsenault, Kelly Harper, Claire M Dubois
The pH-dependent partitioning of chemotherapeutic drugs is a fundamental yet understudied drug distribution mechanism that may underlie the low success rates of current approaches to counter multidrug resistance (MDR). This mechanism is influenced by the hypoxic tumour microenvironment and results in selective trapping of weakly basic drugs into acidified compartments such as the extracellular environment. Here we report that hypoxia not only leads to acidification of the tumour microenvironment but also induces endosome hyperacidification...
June 21, 2017: Nature Communications
https://www.readbyqxmd.com/read/28289928/human-rotavirus-strain-wa-downregulates-nhe1-and-nhe6-expressions-in-rotavirus-infected-caco-2-cells
#7
Honglang Chen, Lijun Song, Guixian Li, Wenfeng Chen, Shumin Zhao, Ruoxia Zhou, Xiaoying Shi, Zhenying Peng, Wenchang Zhao
Rotavirus (RV) is the most common cause of severe gastroenteritis and fatal dehydration in human infants and neonates of different species. However, the pathogenesis of rotavirus-induced diarrhea is poorly understood. Secretory diarrhea caused by rotavirus may lead to a combination of excessive secretion of fluid and electrolytes into the intestinal lumen. Fluid absorption in the small intestine is driven by Na+ -coupled transport mechanisms at the luminal membrane, including Na+ /H+ exchanger (NHE). Here, we performed qRT-PCR to detect the transcription of NHEs...
June 2017: Virus Genes
https://www.readbyqxmd.com/read/27590723/a-christianson-syndrome-linked-deletion-mutation-%C3%A2-287-es-288-in-slc9a6-disrupts-recycling-endosomal-function-and-elicits-neurodegeneration-and-cell-death
#8
Alina Ilie, Andy Y L Gao, Jonathan Reid, Annie Boucher, Cassandra McEwan, Hervé Barrière, Gergely L Lukacs, R Anne McKinney, John Orlowski
BACKGROUND: Christianson Syndrome, a recently identified X-linked neurodevelopmental disorder, is caused by mutations in the human gene SLC9A6 encoding the recycling endosomal alkali cation/proton exchanger NHE6. The patients have pronounced limitations in cognitive ability, motor skills and adaptive behaviour. However, the mechanistic basis for this disorder is poorly understood as few of the more than 20 mutations identified thus far have been studied in detail. METHODS: Here, we examined the molecular and cellular consequences of a 6 base-pair deletion of amino acids Glu(287) and Ser(288) (∆ES) in the predicted seventh transmembrane helix of human NHE6 expressed in established cell lines (CHO/AP-1, HeLa and neuroblastoma SH-SY5Y) and primary cultures of mouse hippocampal neurons by measuring levels of protein expression, stability, membrane trafficking, endosomal function and cell viability...
September 2, 2016: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/27123481/exonic-deletion-of-slc9a9-in-autism-with-epilepsy
#9
Meeta Cardon, Karen D Evankovich, J Lloyd Holder
Genes encoding proteins critical for intracellular vesicular transport are an emerging area of importance for neurologists. In particular, proteins that create and maintain the correct compartmental pH, such as the endosomal Na(+)/H(+) exchangers (NHEs), have been implicated in a wide range of human diseases, including cardiovascular, inflammatory bowel, renal, and neurologic disorders, which demonstrates the critical cellular function of these proteins.(1-3) Two NHEs, NHE6 and NHE9, have been linked to neurologic disorders in children...
April 2016: Neurology. Genetics
https://www.readbyqxmd.com/read/26965387/emerging-roles-of-na%C3%A2-%C2%BA-h%C3%A2-%C2%BA-exchangers-in-epilepsy-and-developmental-brain-disorders
#10
REVIEW
Hanshu Zhao, Karen E Carney, Lindsay Falgoust, Jullie W Pan, Dandan Sun, Zhongling Zhang
Epilepsy is a common central nervous system (CNS) disease characterized by recurrent transient neurological events occurring due to abnormally excessive or synchronous neuronal activity in the brain. The CNS is affected by systemic acid-base disorders, and epileptic seizures are sensitive indicators of underlying imbalances in cellular pH regulation. Na(+)/H(+) exchangers (NHEs) are a family of membrane transporter proteins actively involved in regulating intracellular and organellar pH by extruding H(+) in exchange for Na(+) influx...
March 2016: Progress in Neurobiology
https://www.readbyqxmd.com/read/26531385/novel-endosomal-mechanisms-in-human-axonal-growth-mediated-by-christianson-syndrome-protein-nhe6
#11
Eric M Morrow, Sofia B Lizarraga, Qing Ouyang
No abstract text is available yet for this article.
December 2015: International Journal of Developmental Neuroscience
https://www.readbyqxmd.com/read/25561733/the-na-h-exchanger-nhe6-modulates-endosomal-ph-to-control-processing-of-amyloid-precursor-protein-in-a-cell-culture-model-of-alzheimer-disease
#12
Hari Prasad, Rajini Rao
Early intervention may be key to safe and effective therapies in patients with Alzheimer disease. Endosomal dysfunction is an early step in neurodegeneration. Endosomes are a major site of production of Aβ peptide from the processing of amyloid precursor protein (APP) by clipping enzymes (β- and γ-secretases). The β-secretase enzyme BACE1 requires acidic lumen pH for optimum function, and acid pH promotes Aβ aggregation. The Na(+)/H(+) exchanger NHE6 provides a leak pathway for protons, limiting luminal acidification by proton pumps...
February 27, 2015: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/25044251/genetic-and-phenotypic-diversity-of-nhe6-mutations-in-christianson-syndrome
#13
Matthew F Pescosolido, David M Stein, Michael Schmidt, Christelle Moufawad El Achkar, Mark Sabbagh, Jeffrey M Rogg, Umadevi Tantravahi, Rebecca L McLean, Judy S Liu, Annapurna Poduri, Eric M Morrow
OBJECTIVE: Recently, Christianson syndrome (CS) has been determined to be caused by mutations in the X-linked Na(+) /H(+) exchanger 6 (NHE6). We aimed to determine the diagnostic criteria and mutational spectrum for CS. METHODS: Twelve independent pedigrees (14 boys, age = 4-19 years) with mutations in NHE6 were administered standardized research assessments, and mutations were characterized. RESULTS: The mutational spectrum was composed of 9 single nucleotide variants, 2 indels, and 1 copy number variation deletion...
October 2014: Annals of Neurology
https://www.readbyqxmd.com/read/25002837/an-inside-job-how-endosomal-na-h-exchangers-link-to-autism-and-neurological-disease
#14
REVIEW
Kalyan C Kondapalli, Hari Prasad, Rajini Rao
Autism imposes a major impediment to childhood development and a huge emotional and financial burden on society. In recent years, there has been rapidly accumulating genetic evidence that links the eNHE, a subset of Na(+)/H(+) exchangers that localize to intracellular vesicles, to a variety of neurological conditions including autism, attention deficit hyperactivity disorder (ADHD), intellectual disability, and epilepsy. By providing a leak pathway for protons pumped by the V-ATPase, eNHE determine luminal pH and regulate cation (Na(+), K(+)) content in early and recycling endosomal compartments...
2014: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/24767989/the-intracellular-na-h-exchanger-nhe7-effects-a-na-coupled-but-not-k-coupled-proton-loading-mechanism-in-endocytosis
#15
Nina Milosavljevic, Michaël Monet, Isabelle Léna, Frédéric Brau, Sandra Lacas-Gervais, Sylvain Feliciangeli, Laurent Counillon, Mallorie Poët
Vesicular H(+)-ATPases and ClC-chloride transporters are described to acidify intracellular compartments, which also express the highly conserved Na(+)/H(+) exchangers NHE6, NHE7, and NHE9. Mutations of these exchangers cause autism-spectrum disorders and neurodegeneration. NHE6, NHE7, and NHE9 are hypothesized to exchange cytosolic K(+) for H(+) and alkalinize vesicles, but this notion has remained untested in K(+) because their intracellular localization prevents functional measurements. Using proton-killing techniques, we selected a cell line that expresses wild-type NHE7 at the plasma membrane, enabling measurement of the exchanger's transport parameters...
May 8, 2014: Cell Reports
https://www.readbyqxmd.com/read/24630051/a-novel-mutation-in-the-endosomal-na-h-exchanger-nhe6-slc9a6-causes-christianson-syndrome-with-electrical-status-epilepticus-during-slow-wave-sleep-eses
#16
Ginevra Zanni, Sabina Barresi, Roni Cohen, Nicola Specchio, Lina Basel-Vanagaite, Enza Maria Valente, Avinoam Shuper, Federico Vigevano, Enrico Bertini
Mutations in the solute carrier family 9, subfamily A member 6 (SLC9A6) gene, encoding the endosomal Na+/H+ exchanger 6 (NHE6) are associated with Christianson syndrome, a syndromic form of X-linked intellectual disability characterized by microcephaly, severe global developmental delay, autistic behavior, early onset seizures and ataxia. In a 7-year-old boy with characteristic clinical and neuroimaging features of Christianson syndrome and epileptic encephalopathy with continuous spikes and waves during sleep, we identified a novel splice site mutation (IVS10-1G>A) in SLC9A6...
May 2014: Epilepsy Research
https://www.readbyqxmd.com/read/24337822/traditional-and-emerging-roles-for-the-slc9-na-h-exchangers
#17
REVIEW
Daniel G Fuster, R Todd Alexander
The SLC9 gene family encodes Na(+)/H(+) exchangers (NHEs). These transmembrane proteins transport ions across lipid bilayers in a diverse array of species from prokaryotes to eukaryotes, including plants, fungi, and animals. They utilize the electrochemical gradient of one ion to transport another ion against its electrochemical gradient. Currently, 13 evolutionarily conserved NHE isoforms are known in mammals [22, 46, 128]. The SLC9 gene family (solute carrier classification of transporters: www.bioparadigms...
January 2014: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/24094097/acid-indigestion-in-the-endosome-linking-signaling-dysregulation-to-neurodevelopmental-disorders
#18
COMMENT
Chan Choo Yap, Bettina Winckler
The sodium-proton exchanger NHE6 contributes to proper endosomal acidification. NHE6 mutations are also linked to autism-related disorders. In this issue of Neuron, using NHE6-knockout mice, Ouyang et al. (2013) uncover how dysregulation of endosomal pH leads to disturbances in BDNF signaling and neuronal morphogenesis defects.
October 2, 2013: Neuron
https://www.readbyqxmd.com/read/24090639/impaired-posttranslational-processing-and-trafficking-of-an-endosomal-na-h-exchanger-nhe6-mutant-%C3%AE-370-wst-372-associated-with-x-linked-intellectual-disability-and-autism
#19
Alina Ilie, Erica Weinstein, Annie Boucher, R Anne McKinney, John Orlowski
Na(+)/H(+) exchanger NHE6/SLC9A6 is an X-linked gene that is widely expressed and especially abundant in brain, heart and skeletal muscle where it is implicated in endosomal pH homeostasis and trafficking as well as maintenance of cell polarity. Recent genetic studies have identified several mutations in the coding region of NHE6 that are linked with severe intellectual disability, autistic behavior, ataxia and other abnormalities. One such defect consists of an in-frame deletion of three amino acids ((370)Trp-Ser-Thr(372), ΔWST) that adjoin the predicted ninth transmembrane helix of the exchanger...
July 2014: Neurochemistry International
https://www.readbyqxmd.com/read/24035762/christianson-syndrome-protein-nhe6-modulates-trkb-endosomal-signaling-required-for-neuronal-circuit-development
#20
Qing Ouyang, Sofia B Lizarraga, Michael Schmidt, Unikora Yang, Jingyi Gong, Debra Ellisor, Julie A Kauer, Eric M Morrow
Neuronal arborization is regulated by cell-autonomous and nonautonomous mechanisms including endosomal signaling via BDNF/TrkB. The endosomal Na⁺/H⁺ exchanger 6 (NHE6) is mutated in a new autism-related disorder. NHE6 functions to permit proton leak from endosomes, yet the mechanisms causing disease are unknown. We demonstrate that loss of NHE6 results in overacidification of the endosomal compartment and attenuated TrkB signaling. Mouse brains with disrupted NHE6 display reduced axonal and dendritic branching, synapse number, and circuit strength...
October 2, 2013: Neuron
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