NHE9 and Endosomal pH: Converging Mechanisms in Neurodevelopmental, Psychiatric and Neurodegenerative Disorders

The Na⁺(K⁺)/H⁺ exchanger NHE9 (SLC9A9), a key regulator of endosomal pH, is increasingly recognized as a contributor to a shared pathomechanism-endosomal dysfunction-across neurodevelopmental, psychiatric and neurodegenerative disorders. Enriched in the brain, NHE9 acts as a leak pathway for protons to balance vacuolar ATPase-driven acidification, fine-tuning luminal pH essential for synaptic, circuit and behavioural functions. Structurally, NHE9 operates as a dimer via an elevator-like transport mechanism. Functionally, it modulates neuronal and glial processes-such as presynaptic Ca²⁺ dynamics, synaptic vesicle exocytosis, endocytic recycling and glutamate clearance-all critical to neurotransmission and synaptic plasticity. Consequently, NHE9 has been implicated in a range of brain disorders, including autism, schizophrenia and Alzheimer's disease. Genetic studies also associate NHE9 with interferon-β therapy response in multiple sclerosis and chronic pain, underscoring broader neurological significance. Despite growing evidence, mechanistic links between NHE9 dysfunction and clinical phenotypes across the neurodevelopmental-neurodegenerative continuum remain poorly defined. This narrative review synthesizes conceptual advances and findings from cellular models, animal studies and human genetics to construct a model positioning NHE9 dysfunction as an upstream pathogenic factor across diverse brain disorders. Critical knowledge gaps include genotype-phenotype correlations, isoform-specific roles and neuron-glia interactions. Patient-derived systems and in vivo models will be essential for elucidating mechanisms and developing targeted therapies. Identifying a convergent mechanism of endosomal pH dysregulation across disorders would enable pharmacological control of NHE9. Future research should define strategies to restore endosomal homeostasis, with potential to interrupt pathogenic feedforward loops that worsen symptoms and drive disease progression.