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.

中文翻译：

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组胺合成和转运通过双重质量控制系统耦合在轴突末端。


由从头合成产生的单胺类神经递质被迅速运输并储存到轴突末梢的突触囊泡中。这种运输对于维持突触传递和限制单胺的毒性作用都是必不可少的。在这里，组氨酸脱羧酶 （HDC） 合成单胺组胺并随后将组胺加载到突触囊泡中，结果显示，在果蝇光感受器末端内在物理和功能上是耦合的。这个过程需要 HDC 通过与 N-乙基马来酰亚胺敏感融合蛋白 1 （NSF1） 的相互作用锚定到突触小泡上。HDC 与突触小泡分离会破坏视觉突触传递并导致组胺的体细胞积累，从而导致视网膜变性。我们进一步鉴定了由 E3 泛素连接酶、精华纯度 （POE） 介导的蛋白酶体降解系统，该系统从体细胞中清除错位的 HDC，从而消除组胺的细胞毒性作用。综上所述，我们的结果揭示了 HDC 易位和降解的双重机制，可确保组胺合成限制到轴突末端，同时快速加载到突触小泡中。这对于维持神经传递和防止细胞毒性单胺至关重要。