Brain-derived neurotrophic factor inhibits phenylalanine-induced neuronal apoptosis by preventing RhoA pathway activation.
Phenylketonuria (PKU) is neuropathologically characterized by neuronal cell loss, white matter abnormalities, dendritic simplification, and synaptic density reduction. The neuropathological effect may be due to the 'toxicity' of the high concentration of phenylalanine, while little is known about the related treatments to block this effect. In this study, we reported that brain-derived growth factor (BDNF) protected neurons from phenylalanine-induced apoptosis and inhibition of Trk receptor by K252a or downregulation of TrkB abrogated the effect of BDNF. We further demonstrated that phenylalanine-induced RhoA activation and myosin light chain phosphorylation were inhibited by pretreatment with BDNF, while phenylalanine activates the mitochondria-mediated apoptosis through the RhoA/Rho-associated kinase pathway. Thus our studies indicate that the protective effect of BDNF against phenylalanine-induced neuronal apoptosis is probably mediated by suppression of RhoA signaling pathway via TrkB receptor. Taken together, these findings suggest a potential neuroprotective action of BDNF in prevention and treatment of PKU brain injury.
Zhang
Yongjun
Y
XinHua Hospital, Shanghai Institute for Pediatric Research, Shanghai Jiaotong University School of Medicine, Kongjiang Road 1665#, 200092, Shanghai, China. zhangyongjun@sjtu.edu.cn
Zhao
Jing
J
Wang
Jing
J
Jiao
Xianting
X
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001711:Biotransformation / Q000187:drug effects; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D008928:Mitochondria / Q000378:metabolism; D018994:Myosin Light Chains / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D010649:Phenylalanine / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D010766:Phosphorylation; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism*
D019208:Brain-Derived Neurotrophic Factor; D018994:Myosin Light Chains; D010649:Phenylalanine; D020813:Receptor, trkB; D020558:GTP Phosphohydrolases; D020742:rhoA GTP-Binding Protein