Mitogen-activated protein kinase activity may not be necessary for the neuropathology of Niemann-Pick type C mice

J Neurochem. 2008 Nov;107(3):814-22. doi: 10.1111/j.1471-4159.2008.05657.x. Epub 2008 Sep 6.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Brain / drug effects
  • Brain / enzymology
  • Brain / pathology
  • Disease Models, Animal
  • Enzyme Inhibitors / administration & dosage*
  • Flavonoids / pharmacology*
  • Immunohistochemistry
  • Immunoprecipitation
  • Injections, Intraventricular
  • Mice
  • Microtubule-Associated Proteins / drug effects
  • Microtubule-Associated Proteins / metabolism
  • Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase 1 / drug effects
  • Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase 3 / drug effects
  • Neurofilament Proteins / drug effects
  • Neurofilament Proteins / metabolism
  • Niemann-Pick Disease, Type C / enzymology*
  • Niemann-Pick Disease, Type C / pathology
  • Oligodendroglia / drug effects
  • Oligodendroglia / metabolism
  • Oligodendroglia / pathology
  • Phosphorylation
  • tau Proteins / drug effects
  • tau Proteins / metabolism

Substances

  • Enzyme Inhibitors
  • Flavonoids
  • Microtubule-Associated Proteins
  • Neurofilament Proteins
  • tau Proteins
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one