Histamine synthesis and transport are coupled in axon terminals via a dual quality control system.

Monoamine neurotransmitters generated by de novo synthesis are rapidly transported and stored into synaptic vesicles at axon terminals. This transport is essential both for sustaining synaptic transmission and for limiting the toxic effects of monoamines. Here, synthesis of the monoamine histamine by histidine decarboxylase (HDC) and subsequent loading of histamine into synaptic vesicles are shown to be physically and functionally coupled within Drosophila photoreceptor terminals. This process requires HDC anchoring to synaptic vesicles via interactions with N-ethylmaleimide-sensitive fusion protein 1 (NSF1). Disassociating HDC from synaptic vesicles disrupts visual synaptic transmission and causes somatic accumulation of histamine, which leads to retinal degeneration. We further identified a proteasome degradation system mediated by the E3 ubiquitin ligase, purity of essence (POE), which clears mislocalized HDC from the soma, thus eliminating the cytotoxic effects of histamine. Taken together, our results reveal a dual mechanism for translocation and degradation of HDC that ensures restriction of histamine synthesis to axonal terminals and at the same time rapid loading into synaptic vesicles. This is crucial for sustaining neurotransmission and protecting against cytotoxic monoamines. Synopsis: Neurotransmitters are key for synaptic transmission at axon terminals, but their transport modalities remain debated. This study demonstrates that coupling of histamine synthesis with its loading into synaptic vesicles by anchoring histidine decarboxylase (HDC) to synaptic vesicles is critical to maintaining neurotransmission and preventing cytotoxic side effects. Coupling histamine synthesis with synaptic vesicle loading is critical for neurotransmitter homeostasis and synaptic transmission. HDC is co-transported with synaptic vesicles to axonal terminals through binding with vesicle-fusing ATPase NSF1. HDC remaining in soma is degraded by the E3 ubiquitin ligase POE via the proteasome. Aberrant accumulation of histamine in the soma is cytotoxic and causes retinal degeneration. Anchoring of histidine decarboxylase to synaptic vesicles is critical to maintaining neurotransmission and preventing cytotoxic side effects. [ABSTRACT FROM AUTHOR]