Tudor Elizabeth L, Perkinton Michael S, Schmidt Anja, Ackerley Steven, Brownlees Janet, Jacobsen Nicholas J O, Byers Helen L, Ward Malcolm, Hall Alan, Leigh P Nigel, Shaw Christopher E, McLoughlin Declan M, Miller Christopher C J
Departments of Neuroscience and Neurology, Institute of Psychiatry, Kings College, London SE5 8AF, United Kingdom.
J Biol Chem. 2005 Oct 14;280(41):34735-40. doi: 10.1074/jbc.M506216200. Epub 2005 Jul 26.
Rac and its downstream effectors p21-activated kinase (PAK) family kinases regulate actin dynamics within growth cones to control neurite outgrowth during development. The activity of Rac is stimulated by guanine nucleotide exchange factors (GEFs) that promote GDP release and GTP binding. ALS2/Alsin is a recently described GEF that contains a central domain that is predicted to regulate the activities of Rac and/or Rho and Cdc42 activities. Mutations in ALS2 cause some recessive familial forms of amyotrophic lateral sclerosis (ALS) but the function of ALS2 is poorly understood. Here we demonstrate that ALS2 is present within growth cones of neurons, in which it co-localizes with Rac. Furthermore, ALS2 stimulates Rac but not Rho or Cdc42 activities, and this induces a corresponding increase in PAK1 activity. Finally, we demonstrate that ALS2 promotes neurite outgrowth. Defects in these functions may therefore contribute to motor neuron demise in ALS.
Rac及其下游效应器p21激活激酶（PAK）家族激酶调节生长锥内的肌动蛋白动力学，以控制发育过程中的神经突生长。Rac的活性受鸟嘌呤核苷酸交换因子（GEF）刺激，GEF促进GDP释放和GTP结合。ALS2/Alsin是最近描述的一种GEF，其包含一个预测可调节Rac和/或Rho以及Cdc42活性的中央结构域。ALS2中的突变会导致某些隐性家族性肌萎缩侧索硬化症（ALS），但对ALS2的功能了解甚少。在这里，我们证明ALS2存在于神经元的生长锥中，在那里它与Rac共定位。此外，ALS2刺激Rac的活性，但不刺激Rho或Cdc42的活性，这会相应地导致PAK1活性增加。最后，我们证明ALS2促进神经突生长。因此，这些功能缺陷可能导致ALS中的运动神经元死亡。
