Mitogen-activated protein kinase activity may not be necessary for the neuropathology of Niemann-Pick type C mice.
Hyperphosphorylation of neurofilament and tau, and formation of cytoskeletal lesions, are notable features of several human neurodegenerative diseases, including Niemann-Pick Disease Type C (NPC). Previous studies suggested that the MAPKs, extracellular signal regulated kinase 1 and 2 (ERK1/2) may play a significant role in this aspect of NPC. To test this idea, we treated npc mice with PD98059, a specific and potent inhibitor of MAPK activation. Although activity of ERK1/2 was inhibited by 40%, a 2-week intracerebroventricular infusion of PD98059 just prior to onset of cytoskeletal pathology and symptoms in npc mice did not delay or inhibit prominent hallmarks of NPC. Unexpectedly, ERK1/2 inhibition led to aggravation of tau hyperphosphorylation, particularly in oligodendroctyes, in a manner similar to that of certain human tauopathies. Our results suggest that ERK1/2 does not play a major role in NPC neuropathology, and therefore, that MAPK inhibition is unlikely to be a useful strategy for managing the disease.
Zhang
Min
M
Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. mzhang@tjh.tjmu.edu.cn
Hallows
Janice L
JL
Wang
Xuezhen
X
Bu
Bitao
B
Wang
Wei
W
Vincent
Inez
I
D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005419:Flavonoids / Q000494:pharmacology*; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007276:Injections, Intraventricular; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000187:drug effects / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors* / Q000187:drug effects; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors* / Q000187:drug effects; D016900:Neurofilament Proteins / Q000187:drug effects / Q000378:metabolism; D052556:Niemann-Pick Disease, Type C / Q000201:enzymology* / Q000473:pathology; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D016875:tau Proteins / Q000187:drug effects / Q000378:metabolism
D004791:Enzyme Inhibitors; D005419:Flavonoids; D008869:Microtubule-Associated Proteins; D016900:Neurofilament Proteins; D016875:tau Proteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one