Manser Catherine, Stevenson Alison, Banner Steven, Davies Jennifer, Tudor Elizabeth L, Ono Yoshitaka, Leigh P Nigel, McLoughlin Declan M, Shaw Christopher E, Miller Christopher C J
MRC Centre for Neurodegeneration Research, Department of Neuroscience P037, Institute of Psychiatry, King's College, De Crespigny Park, Denmark Hill, London SE58AF, United Kingdom.
Biosignal Research Center, Kobe University, Kobe 657-8501, Japan.
FEBS Lett. 2008 Jun 25;582(15):2303-2308. doi: 10.1016/j.febslet.2008.05.034. Epub 2008 Jun 2.
Neurofilaments are synthesised in neuronal cell bodies and then transported through axons. Damage to neurofilament transport is seen in amyotrophic lateral sclerosis (ALS). Here, we show that PKN1, a neurofilament head-rod domain kinase is cleaved and activated in SOD1G93A transgenic mice that are a model of ALS. Moreover, we demonstrate that glutamate, a proposed toxic mechanism in ALS leads to caspase cleavage and disruption of PKN1 in neurons. Finally, we demonstrate that a cleaved form of PKN1 but not wild-type PKN1 disrupts neurofilament organisation and axonal transport. Thus, deregulation of PKN1 may contribute to the pathogenic process in ALS.
神经丝在神经元细胞体中合成，然后通过轴突运输。在肌萎缩侧索硬化症（ALS）中可见神经丝运输受损。在此，我们表明，PKN1，一种神经丝头杆结构域激酶，在作为ALS模型的SOD1G93A转基因小鼠中被切割并激活。此外，我们证明，谷氨酸，一种被认为在ALS中起作用的毒性机制，会导致神经元中PKN1的半胱天冬酶切割和破坏。最后，我们证明，PKN1的切割形式而非野生型PKN1会破坏神经丝组织和轴突运输。因此，PKN1的失调可能促成了ALS的致病过程。
