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Mitogen‐activated protein kinase activity may not be necessary for the neuropathology of Niemann–Pick type C mice
Author(s) -
Zhang Min,
Hallows Janice L.,
Wang Xuezhen,
Bu Bitao,
Wang Wei,
Vincent Inez
Publication year - 2008
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2008.05657.x
Subject(s) - hyperphosphorylation , neuropathology , mapk/erk pathway , kinase , cytoskeleton , mitogen activated protein kinase , biology , neuroscience , protein kinase a , medicine , neurofilament , microbiology and biotechnology , endocrinology , cancer research , disease , biochemistry , cell , immunohistochemistry
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.