Kinases and Brain Development Laboratory, The Francis Crick Institute, London NW1 1AT, United Kingdom.
Kinases and Brain Development Laboratory, The Francis Crick Institute, London NW1 1AT, United Kingdom.
Prog Neuropsychopharmacol Biol Psychiatry. 2018 Jun 8;84(Pt B):343-352. doi: 10.1016/j.pnpbp.2017.12.006. Epub 2017 Dec 11.
Neuronal morphogenesis and synapse development is essential for building a functioning nervous system, and defects in these processes are associated with neurological disorders. Our understanding of molecular components and signalling events that contribute to neuronal development and pathogenesis is limited. Genes associated with neurodevelopmental and neurodegenerative diseases provide entry points for elucidating molecular events that contribute to these conditions. Several protein kinases, enzymes that regulate protein function by phosphorylating their substrates, are genetically linked to neurological disorders. Identifying substrates of these kinases is key to discovering their function and providing insight for possible therapies. In this review, we describe how various methods for kinase-substrate identification helped elucidate kinase signalling pathways important for neuronal development and function. We describe recent advances on roles of kinases TAOK2, TNIK and CDKL5 in neuronal development and the converging pathways of LRRK2, PINK1 and GAK in Parkinson's Disease.
神经元形态发生和突触发育对于构建功能正常的神经系统至关重要,这些过程中的缺陷与神经紊乱有关。我们对于促进神经元发育和发病机制的分子成分和信号事件的理解还很有限。与神经发育和神经退行性疾病相关的基因为阐明导致这些疾病的分子事件提供了切入点。几种蛋白激酶,即通过使底物磷酸化来调节其功能的酶,在遗传上与神经紊乱相关。鉴定这些激酶的底物是发现其功能并为可能的治疗方法提供深入了解的关键。在这篇综述中,我们描述了各种用于激酶-底物鉴定的方法如何有助于阐明对神经元发育和功能很重要的激酶信号通路。我们描述了激酶 TAOK2、TNIK 和 CDKL5 在神经元发育中的最新作用,以及 LRRK2、PINK1 和 GAK 在帕金森病中的汇聚途径。