Functional evaluation of autism-associated mutations in NHE9

Kondapalli, Kalyan C.; Hack, Anniesha; Schushan, Maya; Landau, Meytal; Ben‐Tal, Nir; Rao, Rajini

doi:10.1038/ncomms3510

Cited by 91 publications

(182 citation statements)

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“…Due to their distinct localization to specific types of organelles it is likely that intracellular NHEs play a critical part in the regulation of organellar pH. In support of this, overexpression or loss of intracellular NHEs alters organellar pH [113,35,130,80]. This concept is however challenged by studies where knock-down or loss of individual organelle-specific NHEs had no effect on pH [38,147,52].…”

Section: Intracellular Nhesmentioning

confidence: 99%

“…NHE9 localizes to sorting and recycling endosomes and its overexpression was shown to lead to endosomal alkalinization in COS-7 cells and primary astrocytes, whereas its knock-down induced endosomal acidification in primary astrocytes [113,80]. One exeption to the intracellular localization of NHE9 has thus far been reported.…”

Section: Slc9a9 -Nhe9mentioning

confidence: 99%

“…An NHE9 mutation was also found in a rat model of ADHD [189]. Kondapalli et al recently investigated 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 the functional consequences of human NHE9 missense mutations in astrocytes [80]. Overexpression of WT but not of NHE9 mutants in astrocytes caused endosomal alkalinization and enhanced transferrin and glutamate uptake indicating that the three missense mutations found in humans are loss-of-function mutations.…”

Section: Slc9a9 -Nhe9mentioning

confidence: 99%

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Traditional and emerging roles for the SLC9 Na+/H+ exchangers

Fuster

Alexander

2013

Pflugers Arch - Eur J Physiol

141

122

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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 [46,22,128]. The SLC9 gene family (solute carrier classification of transporters:www.bioparadigms.org) is divided into three subgroups [46]. The SLC9A subgroup encompasses plasmalemmal isoforms NHE1-5 (SLC9A1-5) and the predominantly intracellular isoforms NHE6-9 (SLC9A6-9). The SLC9B subgroup consists of two recently cloned isoforms, NHA1 and NHA2 (SLC9B1 and SLC9B2, respectively). The SLC9C subgroup consist of a sperm specific plasmalemmal NHE (SLC9C1) and a putative NHE, SLC9C2, for which there is currently no functional data [46].NHEs participate in the regulation of cytosolic and organellar pH as well as cell volume. In the intestine and kidney, NHEs are critical for transepithelial movement of Na + and HCO 3 -and thus for whole body volume and acid-base homeostasis [46]. Mutations in the NHE6 or NHE9 genes cause neurological disease in humans and are currently the only NHEs directly linked to human disease.However, it is becoming increasingly apparent that members of this gene family contribute to the pathophysiology of multiple human diseases.

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Section: Intracellular Nhesmentioning

confidence: 99%

Section: Slc9a9 -Nhe9mentioning

confidence: 99%

Section: Slc9a9 -Nhe9mentioning

confidence: 99%

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Traditional and emerging roles for the SLC9 Na+/H+ exchangers

Fuster

Alexander

2013

Pflugers Arch - Eur J Physiol

141

122

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“…On the other hand, loss of NHE9 exchanger function as a result of mutations in SLC9A9 leads to hyperacidification of sorting endosomes (27). Functional evaluation of these autismassociated mutations in astrocytes showed that these cells lose their ability to clear glutamate to a significant extent as a consequence of dysregulated trafficking of glutamate transporter (GLAST) (27). Moreover, global knock-out SLC9A9 mice (Slc9a9 KO) show traits of autism spectrum and attention deficit hyperactivity disorder (29).…”

mentioning

confidence: 99%

Na+/H+ Exchanger 9 Regulates Iron Mobilization at the Blood-Brain Barrier in Response to Iron Starvation

Beydoun¹,

Hamood²,

Zubieta

et al. 2017

Journal of Biological Chemistry

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Edited by Paul E. FraserIron is essential for brain function, with loss of iron homeostasis in the brain linked to neurological diseases ranging from rare syndromes to more common disorders, such as Parkinson's and Alzheimer's diseases. Iron entry into the brain is regulated by the blood-brain barrier (BBB). Molecular mechanisms regulating this transport are poorly understood. Using an in vitro model of the BBB, we identify NHE9, an endosomal cation/proton exchanger, as a novel regulator of this system. Human brain microvascular endothelial cells (hBMVECs) that constitute the BBB receive brain iron status information via paracrine signals from ensheathing astrocytes. In hBMVECs, we show that NHE9 expression is up-regulated very early in a physiological response invoked by paracrine signals from iron-starved astrocytes. Ectopic expression of NHE9 in hBMVECs without external cues induced up-regulation of the transferrin receptor (TfR) and down-regulation of ferritin, leading to an increase in iron uptake. Mechanistically, we demonstrate that NHE9 localizes to recycling endosomes in hBMVECs where it raises the endosomal pH. The ensuing alkalization of the endosomal lumen increased translocation of TfRs to the hBMVEC membrane. TfRs on the membrane were previously shown to facilitate both recycling-dependent and -independent iron uptake. We propose that NHE9 regulates TfR-dependent, recycling-independent iron uptake in hBMVECs by fine-tuning the endosomal pH in response to paracrine signals and is therefore an important regulator in iron mobilization pathway at the BBB.There is high demand for iron in the brain, one of the most metabolically active organs in the body (1, 2). Iron is a co-factor of several proteins involved in specialized brain cell functions such as synthesis of neurotransmitters and myelination (3-5). Iron is also necessary for housekeeping functions such as mitochondrial respiration and DNA synthesis, crucial for brain function (5). Insufficient or surplus iron in the brain has been associated with various neurological diseases (6 -10). Although iron deficiency is associated with cognitive and brain structural deficits, excess brain iron is implicated in Alzheimer's, Parkinson's, and other neurodegenerative diseases (10, 11). Therefore, it is not surprising that iron levels are tightly regulated in the brain (10).Iron entry into the brain is regulated by the blood-brain barrier (BBB) 3 (10). This physiological barrier is characterized by tight junctions between brain microvascular endothelial cells (BMVECs) that block passive diffusion of iron into the brain (12). BMVECs are polarized cells with one surface (apical) facing the blood and the other (basal or abluminal) facing interstitial fluid of the brain. BMVECs and ensheathing astrocytes form the regulatory axis of the BBB, modulating iron transport from blood into the brain interstitium (2, 13). It is now known that BMVECs are the focal point for regulation of cerebral iron homeostasis and not mere conduits for iron transport (14). Paracrine fac...

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“…The specific pH of each organelle is determined by a balance of V-ATPase-mediated proton pumping and a "proton leak" pathway (13)(14)(15). Several studies in yeast (16) and mammalian cells (14,15,(17)(18)(19) demonstrated that overexpression or knockdown of organellar NHEs leads to alkalinization or acidification of the organellar lumen, respectively, suggesting that these transporters provide a proton leak. The importance of organellar NHEs is underscored by mutations in NHE6 and NHE9 that lead to neurological disorders such as autism and epilepsy in humans (20,21).…”

mentioning

confidence: 99%