Synaptojanin1 (synj1) is a phosphoinositide phosphatase with dual SAC1 and 5′-phosphatase enzymatic activities in regulating phospholipid signaling. The brain-enriched isoform has been shown to participate in synaptic vesicle (SV) recycling. More recently, recessive human mutations were identified in the two phosphatase domains of SYNJ1, including R258Q, R459P and R839C, which are linked to rare forms of early-onset Parkinsonism. We now demonstrate that Synj1 heterozygous deletion (Synj1^+/−), which is associated with an impaired 5′-phosphatase activity, also leads to Parkinson’s disease (PD)-like pathologies in mice. We report that male Synj1^+/− mice display age-dependent motor function abnormalities as well as alpha-synuclein accumulation, impaired autophagy and dopaminergic terminal degeneration. Synj1^+/− mice contain elevated 5′-phosphatase substrate, PI(4,5)P₂, particularly in the midbrain neurons. Moreover, pharmacological elevation of membrane PI(4,5)P₂ in cultured neurons impairs SV endocytosis, specifically in midbrain neurons, and further exacerbates SV trafficking defects in Synj1^+/− midbrain neurons. We demonstrate down-regulation of SYNJ1 transcript in a subset of sporadic PD brains, implicating a potential role of Synj1 deficiency in the decline of dopaminergic function during aging.

中文翻译：

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Synj1 单倍剂量不足导致小鼠多巴胺神经元脆弱性和 α-突触核蛋白积累。

Synaptojanin1 (synj1) 是一种磷酸肌醇磷酸酶，在调节磷脂信号传导方面具有双重 SAC1 和 5'-磷酸酶活性。已显示富含大脑的同种型参与突触小泡 (SV) 回收。最近，在SYNJ1的两个磷酸酶结构域中发现了隐性人类突变，包括 R258Q、R459P 和 R839C，它们与罕见的早发性帕金森病有关。我们现在证明Synj1杂合缺失 ( Synj1 ^+/- ) 与 5'-磷酸酶活性受损相关，也会导致小鼠帕金森病 (PD) 样病变。我们报告男性Synj1 ^+/-小鼠表现出年龄依赖性运动功能异常以及 α-突触核蛋白积累、自噬受损和多巴胺能终末变性。Synj1 ^+/-小鼠含有升高的 5'-磷酸酶底物 PI(4,5)P ₂，尤其是在中脑神经元中。此外，培养神经元中膜 PI(4,5)P _{2 的}药理学升高会损害 SV 内吞作用，特别是在中脑神经元中，并进一步加剧Synj1 ^+/-中脑神经元中的SV 运输缺陷。我们证明了SYNJ1转录本在一部分散发性 PD 大脑中的下调，暗示Synj1缺乏在衰老过程中多巴胺能功能下降中的潜在作用。