Saenz Jacqueline, Khezerlou Elnaz, Aggarwal Meha, Shaikh Amina, Ganti Naga, Herborg Freja, Pan Ping-Yue
Department of Neuroscience and Cell Biology, Rutgers University Robert Wood Johnson Medical School, 675 Hoes Lane West, Piscataway, NJ, 08854, USA.
Rutgers Graduate School of Biomedical Sciences, Molecular Biosciences Graduate Program, 675 Hoes Lane West, Piscataway, NJ, 08854, USA.
NPJ Parkinsons Dis. 2024 Aug 8;10(1):148. doi: 10.1038/s41531-024-00769-0.
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)P-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（突触素1/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，在Synj1单倍体不足（Synj1+/-）神经元中，诱发多巴胺快速耗竭，轴突多巴胺转运体（DAT）的维持受损。虽然传统上已知Synj1促进突触小泡的内吞作用，但我们提供了体外和体内证据表明，Synj1单倍体不足导致总DAT增加，但表面DAT减少。Synj1+/-神经元表现出适应不良的DAT转运，这可能导致多巴胺释放改变。我们表明，表面DAT的丧失与5'-磷酸酶活性受损以及Synj1缺乏下游的PI(4,5)P-PKCβ途径过度活跃有关。因此，我们的发现为Synj1调节的DAT转运提供了重要的机制见解，这对于功能失调的多巴胺信号传导不可或缺，这可能与早期帕金森病有关。
