Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Pharmacology, Peripheral Neuropathy Research Center (PNRC), Dong-A University College of Medicine, Busan, Republic of Korea.
Neuron. 2021 Dec 1;109(23):3758-3774.e11. doi: 10.1016/j.neuron.2021.09.031. Epub 2021 Oct 12.
Impairment in glucocerebrosidase (GCase) is strongly associated with the development of Parkinson's disease (PD), yet the regulators responsible for its impairment remain elusive. In this paper, we identify the E3 ligase Thyroid Hormone Receptor Interacting Protein 12 (TRIP12) as a key regulator of GCase. TRIP12 interacts with and ubiquitinates GCase at lysine 293 to control its degradation via ubiquitin proteasomal degradation. Ubiquitinated GCase by TRIP12 leads to its functional impairment through premature degradation and subsequent accumulation of α-synuclein. TRIP12 overexpression causes mitochondrial dysfunction, which is ameliorated by GCase overexpression. Further, conditional TRIP12 knockout in vitro and knockdown in vivo promotes the expression of GCase, which blocks α-synuclein preformed fibrils (α-syn PFFs)-provoked dopaminergic neurodegeneration. Moreover, TRIP12 accumulates in human PD brain and α-synuclein-based mouse models. The identification of TRIP12 as a regulator of GCase provides a new perspective on the molecular mechanisms underlying dysfunctional GCase-driven neurodegeneration in PD.
葡萄糖脑苷脂酶 (GCase) 的功能障碍与帕金森病 (PD) 的发生密切相关，但负责其功能障碍的调节因子仍不清楚。在本文中，我们确定 E3 连接酶甲状腺激素受体相互作用蛋白 12 (TRIP12) 是 GCase 的关键调节因子。TRIP12 与 GCase 相互作用，并在赖氨酸 293 处泛素化 GCase，通过泛素蛋白酶体降解来控制其降解。TRIP12 泛素化的 GCase 通过过早降解和随后α-突触核蛋白的积累导致其功能障碍。TRIP12 的过表达导致线粒体功能障碍，而过表达 GCase 可改善这种功能障碍。此外，体外条件性 TRIP12 敲除和体内敲低促进 GCase 的表达，从而阻止α-突触核蛋白预形成纤维 (α-syn PFFs) 引起的多巴胺能神经退行性变。此外，TRIP12 在人 PD 脑中积累，并且在基于α-突触核蛋白的小鼠模型中积累。将 TRIP12 鉴定为 GCase 的调节剂为 PD 中 GCase 驱动的神经退行性变的功能障碍的分子机制提供了新的视角。
