. Tyrosine 394 is phosphorylated in Alzheimer's paired helical filament tau and in fetal tau with c-Abl as the candidate tyrosine kinase. J Neurosci. 2005 Jul 13;25(28):6584-93. PubMed.

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Comments

  1. This study is very interesting. It seems that increased Aβ may be directly involved in tau pathology due to the fact that it increases expression of c-Abl, which may phosphorylate tau.

    Zeng et al. (1) find that TopBP1 is a repressor of c-Abl expression. What is happening with TopBP1 expression in AD?

    Myc transactivation by Miz-1 is negatively regulated by association with topoisomerase II binding protein (TopBP1) (2) and MIZ-1 appears to be regulated by association with microtubules (3).

    Liu et al. (4) report that TopBP1 functions as a critical modulator and serves as a negative feedback regulator of E2F1 by inhibiting E2F1-dependent apoptosis during G1/S transition as well as DNA damage to promote cell survival.

    The Alvarez group (5) reporting that Aβ peptide fibrils induced an increase of c-Abl activity and that neuronal cell death induced by Aβ fibrils was prevented by the inhibition of c-Abl with Gleevec has me wondering whether TopBP1 may be a pharmacological target in AD. Might that circumvent the problem associated with Gleevec's inability to cross the BBB?

    References:

    . Identification of TopBP1 as a c-Abl-interacting protein and a repressor for c-Abl expression. J Biol Chem. 2005 Aug 12;280(32):29374-80. PubMed.

    . Negative regulation of the mammalian UV response by Myc through association with Miz-1. Mol Cell. 2002 Sep;10(3):509-21. PubMed.

    . Transcription factor MIZ-1 is regulated via microtubule association. Mol Cell. 2001 Aug;8(2):339-49. PubMed.

    . TopBP1 recruits Brg1/Brm to repress E2F1-induced apoptosis, a novel pRb-independent and E2F1-specific control for cell survival. Genes Dev. 2004 Mar 15;18(6):673-86. PubMed.

    . Activation of the neuronal c-Abl tyrosine kinase by amyloid-beta-peptide and reactive oxygen species. Neurobiol Dis. 2004 Nov;17(2):326-36. PubMed.

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