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

ABSTRACT 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 Ca 2+ 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 multipl