Institute for Biomedicine, Eurac Research - Affiliated Institute of the University of Lübeck, via Volta 21, Bolzano, 39100, Italy.
Neurotherapeutics. 2023 Jan;20(1):127-139. doi: 10.1007/s13311-022-01290-z. Epub 2022 Sep 9.
The discovery of mutations in LRRK2 and GBA1 that are linked to Parkinson's disease provided further evidence that autophagy and lysosome pathways are likely implicated in the pathogenic process. Their protein products are important regulators of lysosome function. LRRK2 has kinase-dependent effects on lysosome activity, autophagic efficacy and lysosomal Ca signaling. Glucocerebrosidase (encoded by GBA1) is a hydrolytic enzyme contained in the lysosomes and contributes to the degradation of alpha-synuclein. PD-related mutations in LRRK2 and GBA1 slow the degradation of alpha-synuclein, thus directly implicating the dysfunction of the process in the neuropathology of Parkinson's disease. The development of genetic rodent models of LRRK2 and GBA1 provided hopes of obtaining reliable preclinical models in which to study pathogenic processes and perform drug validation studies. Here, I will review the extensive characterization of these models, their impact on understanding lysosome alterations in the course of Parkinson's disease and what novel insights have been obtained. In addition, I will discuss how these models fare with respect to the features of a "gold standard" animal models and what could be attempted in future studies to exploit LRRK2 and GBA1 rodent models in the fight against Parkinson's disease.
LRRK2 和 GBA1 突变的发现与帕金森病有关，这进一步表明自噬和溶酶体途径可能与发病机制有关。它们的蛋白产物是溶酶体功能的重要调节剂。LRRK2 对溶酶体活性、自噬效率和溶酶体 Ca 信号具有激酶依赖性影响。葡萄糖脑苷脂酶（由 GBA1 编码）是溶酶体中的一种水解酶，有助于α-突触核蛋白的降解。LRRK2 和 GBA1 中的 PD 相关突变会减缓α-突触核蛋白的降解，从而直接表明该过程的功能障碍与帕金森病的神经病理学有关。LRRK2 和 GBA1 的遗传啮齿动物模型的开发为获得可靠的临床前模型提供了希望，这些模型可用于研究发病机制并进行药物验证研究。在这里，我将回顾这些模型的广泛特征，它们对理解帕金森病过程中溶酶体改变的影响，以及获得了哪些新的见解。此外，我将讨论这些模型在“黄金标准”动物模型的特征方面表现如何，以及在未来的研究中可以尝试利用 LRRK2 和 GBA1 啮齿动物模型来对抗帕金森病。
