Leucine rich repeat kinase 2 (LRRK2) is an enigmatic enzyme and a relevant target for Parkinson's disease (PD). However, despite the significant amount of research done in the past decade, the precise function of LRRK2 remains largely unknown. Moreover, the therapeutic potential of its inhibitors is in its infancy with the first clinical trial having just started. In the present work, the molecular mechanism of LRRK2 in the control of neurogenesis or gliogenesis was investigated. We designed and synthesized novel benzothiazole-based LRRK2 inhibitors and showed that they can modulate the Wnt/β-catenin signaling pathway. Furthermore, compounds 5 and 14 were able to promote neural progenitors proliferation and drive their differentiation toward neuronal and oligodendrocytic cell fates. These results suggest potential new avenues for the application of LRRK2 inhibitors in demyelinating diseases in which oligodendrocyte cell-death is one of the pathological features.

中文翻译：

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基于苯并噻唑的LRRK2抑制剂可作为Wnt增强剂和少突胶质细胞命运的促进剂。

富含亮氨酸的重复激酶2（LRRK2）是一种神秘酶，是帕金森氏病（PD）的相关靶标。然而，尽管在过去十年中进行了大量研究，但LRRK2的确切功能仍然未知。而且，其抑制剂的治疗潜力还处于婴儿期，刚刚开始了第一项临床试验。在目前的工作中，研究了LRRK2在控制神经发生或神经胶质发生中的分子机制。我们设计和合成了新型的基于苯并噻唑的LRRK2抑制剂，并表明它们可以调节Wnt /β-catenin信号通路。此外，化合物5和14能够促进神经祖细胞增殖，并促使其向神经元和少突胶质细胞命运分化。