An inside job: how endosomal Na+/H+ exchangers link to autism and neurological disease

Abstract

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. Loss-of-function mutations in eNHE cause hyperacidification of endosomal lumen, as a result of imbalance in pump and leak pathways. Two isoforms, NHE6 and NHE9 are highly expressed in brain, including hippocampus and cortex. Here, we summarize evidence for the importance of luminal cation content and pH on processing, delivery and fate of cargo. Drawing upon insights from model organisms and mammalian cells we show how eNHE affect surface expression and function of membrane receptors and neurotransmitter transporters. These studies lead to cellular models of eNHE activity in pre- and post-synaptic neurons and astrocytes, where they could impact synapse development and plasticity. The study of eNHE has provided new insight on the mechanism of autism and other debilitating neurological disorders and opened up new possibilities for therapeutic intervention.

The Na+/H+ Exchanger NHE6 Modulates Endosomal pH to Control Processing of Amyloid Precursor Protein in a Cell Culture Model of Alzheimer Disease

“…1B). This distribution is consistent with emerging reports implicating NHE6 function in neurogenesis, spine dynamics, dendritic arborization, and synaptic strength (1,17,31). Similarly, impaired neurogenesis has been reported to occur early in AD pathology (32).…”

“…Structural Modeling and Bioinformatics-Three-dimensional homology model structure of NHE6 was developed using the crystal structure of bacterial cation proton antiporter ortholog Escherichia coli NhaA as a template using multiple state-of-the-art approaches and evolutionary conservation analysis, as described earlier (1,28). A brain RNA sequencing gene expression data set from 578 samples represented as log base 2 of RPKM (reads per kilobase of exon model per million mapped sequence reads) values across different developmental periods and different brain regions was obtained from the BrainSpan atlas (available on the World Wide Web).…”

“…NHE6 is an isoform of the superfamily of Na ϩ /H ϩ exchangers, localizing to early and recycling endosomes, where it exchanges luminal H ϩ for cations (Na ϩ or K ϩ ) (1,2). Endosomal pH is precisely tuned by a combination of inward proton pumping through V-ATPase and outward proton leak via endosomal Na ϩ (K ϩ )/H ϩ exchangers, both mechanisms that are evolutionarily conserved from yeast to plants, fruit fly, and mammals (3).…”

“…Autism spectrum disorder has emerged as a major public health concern worldwide with an urgent unmet need for effective and safe interventions (1). With an aging population, Alzheimer and related neurodegenerative disorders pose a similar challenge (20).…”

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

“…The endosomal lumen is acidified by the V-ATPase (17). NHE9 transports these protons out in exchange for sodium or potassium ions (19,20,47). Therefore, an increase in NHE9 expression caused by iron deprivation signals would result in more alkaline endosomal lumen relative to control.…”