The Parkinson's Disease-Associated Protein Kinase LRRK2 Modulates Notch Signaling through the Endosomal Pathway.
The Parkinson's Disease-Associated Protein Kinase LRRK2 Modulates Notch Signaling through the Endosomal Pathway.
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DOI：
10.1371/journal.pgen.1005503
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发表时间：
2015-09
期刊：
影响因子：
4.5
通讯作者：
Takahashi R
中科院分区：
文献类型：
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作者：
Imai Y;Kobayashi Y;Inoshita T;Meng H;Arano T;Uemura K;Asano T;Yoshimi K;Zhang CL;Matsumoto G;Ohtsuka T;Kageyama R;Kiyonari H;Shioi G;Nukina N;Hattori N;Takahashi R
富含亮氨酸重复激酶 2 (LRRK2) 是家族性和特发性帕金森病 (PD) 发病机制中的关键分子。我们已经鉴定了两种新型 LRRK2 相关蛋白，一种 HECT 型泛素连接酶 HERC2 和一种具有六个重复神经化结构域的适配器样蛋白 NEURL4。 LRRK2 分别通过复合蛋白 (ROC) 结构域和 NEURL4 的 LRRK2 Ras 与 NEURL4 和 HERC2 结合。 HERC2 和 NEURL4 将 LRRK2 连接到细胞囊泡转运途径和 Notch 信号传导，通过该途径，LRRK2 复合物通过调节内体运输来促进 Notch 配体 Delta 样 1 (Dll1)/Delta (Dl) 的再循环。该过程通过稳定 Dll1/D1，通过顺式抑制负向调节 Notch 信号传导，从而加速神经干细胞分化并调节分化的多巴胺能神经元的功能和存活。 LRRK2 的 R1441G ROC 结构域突变体增强了这些作用。这些发现表明，成熟神经元中 Notch 信号的改变是与 LRRK2 相关的 PD 病因的一个组成部分。 LRRK2 与常染色体显性迟发型帕金森病有关，表明 LRRK2 功能获得性突变导致中脑多巴胺能神经元的年龄依赖性变性。在这项研究中，我们描述了两种新型 LRRK2 相关蛋白 HERC2 和 NEURL4，它们分别是泛素连接酶和适配器样蛋白。 HERC2 和 NEURL4 将 LRRK2 引导至 Notch 信号通路，其中 LRRK2-NEURL4-HERC2 复合物通过调节内体运输促进 Notch 配体 Delta-like 1 (Dll1)/Delta (Dl) 的循环。结果，质膜上的 Dll1/D1 量增加，从而通过顺式抑制对 Notch 信号传导产生负面影响。与帕金森病相关的 LRRK2 突变可增强该作用。抑制成人多巴胺能神经元中的 Notch 信号传导会损害其功能和存活。这些发现表明 Notch 通路与帕金森病之间可能存在联系。
Leucine-rich repeat kinase 2 (LRRK2) is a key molecule in the pathogenesis of familial and idiopathic Parkinson’s disease (PD). We have identified two novel LRRK2-associated proteins, a HECT-type ubiquitin ligase, HERC2, and an adaptor-like protein with six repeated Neuralized domains, NEURL4. LRRK2 binds to NEURL4 and HERC2 via the LRRK2 Ras of complex proteins (ROC) domain and NEURL4, respectively. HERC2 and NEURL4 link LRRK2 to the cellular vesicle transport pathway and Notch signaling, through which the LRRK2 complex promotes the recycling of the Notch ligand Delta-like 1 (Dll1)/Delta (Dl) through the modulation of endosomal trafficking. This process negatively regulates Notch signaling through cis-inhibition by stabilizing Dll1/Dl, which accelerates neural stem cell differentiation and modulates the function and survival of differentiated dopaminergic neurons. These effects are strengthened by the R1441G ROC domain-mutant of LRRK2. These findings suggest that the alteration of Notch signaling in mature neurons is a component of PD etiology linked to LRRK2. LRRK2 is linked to autosomal dominant late-onset Parkinson’s disease, suggesting that LRRK2 gain-of-function mutations lead to age-dependent degeneration of the midbrain dopaminergic neurons. In this study, we describe two novel LRRK2-associated proteins HERC2 and NEURL4, which are a ubiquitin ligase and an adaptor-like protein, respectively. HERC2 and NEURL4 direct LRRK2 to Notch signaling pathway, in which the LRRK2-NEURL4-HERC2 complex promotes the recycling of the Notch ligand Delta-like 1 (Dll1)/Delta (Dl) through the modulation of endosomal trafficking. As a result, the amounts of Dll1/D1 on the plasma membrane are increased, which affects negatively Notch signaling through cis-inhibition. The effect is enhanced by a Parkinson’s-disease associated mutation of LRRK2. Inhibition of Notch signaling in adult dopaminergic neurons impairs its functions and survival. These findings indicate a possible link between Notch pathway and Parkinson’s disease.