Missense mutations of PARK20/SYNJ1 (synaptojanin1/Synj1) were found in complex forms of familial Parkinsonism. However, the Synj1-regulated molecular and cellular changes associated with dopaminergic dysfunction remain unknown. We now report a fast depletion of evoked dopamine and impaired maintenance of the axonal dopamine transporter (DAT) in the Synj1 haploinsufficient (Synj1+/−) neurons. While Synj1 has been traditionally known to facilitate the endocytosis of synaptic vesicles, we provide in vitro and in vivo evidence demonstrating that Synj1 haploinsufficiency results in an increase of total DAT but a reduction of the surface DAT. Synj1+/− neurons exhibit maladaptive DAT trafficking, which could contribute to the altered DA release. We showed that the loss of surface DAT is associated with the impaired 5’-phosphatase activity and the hyperactive PI(4,5)P₂–PKCβ pathway downstream of Synj1 deficiency. Thus, our findings provided important mechanistic insight for Synj1-regulated DAT trafficking integral to dysfunctional DA signaling, which might be relevant to early Parkinsonism.

在复杂形式的家族性帕金森病中发现了 PARK20/ SYNJ1 （synaptojanin1/Synj1）的错义突变。然而，与多巴胺能功能障碍相关的 Synj1 调节的分子和细胞变化仍然未知。我们现在报告了Synj1单倍体不足 ( Synj1 + /− ) 神经元中诱发多巴胺的快速消耗和轴突多巴胺转运蛋白 (DAT) 的维持受损。虽然传统上已知 Synj1 可以促进突触小泡的内吞作用，但我们提供的体外和体内证据表明， Synj1单倍体不足会导致总 DAT 增加，但表面 DAT 减少。 Synj1 +/-神经元表现出适应不良的 DAT 运输，这可能导致 DA 释放的改变。我们发现表面 DAT 的缺失与 5'-磷酸酶活性受损以及 Synj1 缺陷下游 PI(4,5)P ₂ –PKCβ 通路过度活跃有关。因此，我们的研究结果为 Synj1 调节的 DAT 运输提供了重要的机制见解，该运输是功能失调的 DA 信号传导的一部分，这可能与早期帕金森病有关。