LDN-73794 Attenuated LRRK2-Induced Degeneration in a <i>Drosophila</i>Parkinson’s Disease Model

• 作者: Dejun Yang Jianqun Yan Loujing Song Sharmila Das Tianxia Li Wanli W. Smith
• 来源期刊: 帕金森(英文)
• 学科: 医学
• 关键词: LRRK2 Parkinson’s Disease LDN-73794 Kinase Activity Neuronal DEGENERATION Dopamine Neuron DROSOPHILA Model
• 年，卷（期）: 2015,（3）
• 页码范围: 49-58
• 页数: 10页
• 分类号: R73

摘要

Parkinson’s disease (PD) is a common neurodegenerative disease with unclear pathogenesis. Currently, there are no disease-modifying neuron-protecting drugs to slow down the neuronal degeneration. Mutations in the leucine-rich repeat kinase 2 (LRRK2) cause genetic forms of PD and contribute to sporadic PD as well. Disruption of LRRK2 kinase functions has become one of the potential mechanisms underlying disease-linked mutation-induced neuronal degeneration. To further characterize the pharmacological effects of a reported LRRK2 kinase inhibitor, LDN-73794, in vitro cell models and a LRRK2 Drosophila PD model were used. LDN-73794 reduced LRRK2 kinase activity in vitro and in vivo. Moreover, LDN-73794 increased survival, improved locomotor activity, and suppressed DA neuron loss in LRRK2 transgenic flies. These results suggest that inhibition of LRRK2 kinase activity can be a potential therapeutic strategy for PD intervention and LDN-73794 could be a potential lead compound for developing neuroprotective therapeutics.