. Gene regulation and DNA damage in the ageing human brain. Nature. 2004 Jun 24;429(6994):883-91. PubMed.

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  1. This recent study provides novel insights into the biology of aging in human brains. However, the comment by Dr. Ming Chen posted July 12 is somewhat misleading. Dr. Chen states that the “age-related downregulation of several protein kinases, especially Cdk5” is very important, because this finding is in “contrast to current enthusiasm that activation of this kinase causes tau hyperphosphorylation.” As such, Dr. Chen concludes that, “if Cdk5 is actually down, then tau hyperphosphorylation would have to be explained by some other models.”

    In fact, the study by Lu et al. does not demonstrate downregulation of Cdk5. Instead, the Cdk5 activator p35 is significantly downregulated in aging brains. The misunderstanding of this point confounds the interpretation of this data by Dr. Chen. Furthermore, Lu et al. suggest that tau is also downregulated, so hyperphosphorylation of tau is unlikely to be relevant, according to Dr. Chen’s argument.

    To date, there is no evidence to suggest that Cdk5/p35 is neurotoxic. In fact, physiological Cdk5/p35 activity has been established as an important regulator of synaptic plasticity, learning, and memory (Li et al., 2001; Fischer et al., 2002; Fischer et al., 2003). Therefore, downregulation of p35 in aging brains is in agreement with the current knowledge about the role of Cdk5/p35 in the adult brain.

    It should be noted that tau is a very poor substrate of Cdk5/p35 in vivo and in vitro (Patrick et al., 1999; Van den Haute et al., 2001; Hashiguchi et al., 2003). On the other hand, the Cdk5/p25 kinase has been shown to be a potent tau kinase. P25 is produced via calpain-mediated cleavage of p35. P25 causes deregulation of Cdk5 activity, as p25 is more stable and displays altered subcellular localization. Thus, the levels of p25 in vivo cannot be assessed by transcriptional profiling, and decreased p35 levels do not necessarily lead to reduced Cdk5 activity in human brains. Notably, we have shown that low levels of p25 production are able to partially compensate the phenotype of p35-deficient mice (Patzke et al., 2003), suggesting that p25 can compensate for loss of p35. This raises the possibility that downregulation of p35 in aging brains may initially induce p25 production as a compensatory effect, which under certain circumstances leads to p25 accumulation and neurodegeneration. This possibility warrants further investigation.

    References:

    Fischer A, Sananbenesi F, Schrick C, Spiess J, Radulovic J. Cyclin-dependent kinase 5 is required for associative learning. J Neurosci. 2002 May 1;22(9):3700-7. Abstract

    Fischer A, Sananbenesi F, Schrick C, Spiess J, Radulovic J. Regulation of contextual fear conditioning by baseline and inducible septo-hippocampal cyclin-dependent kinase 5.
    Neuropharmacology. 2003 Jun;44(8):1089-99. Abstract

    Hashiguchi M, Saito T, Hisanaga S, Hashiguchi T. Truncation of CDK5 activator p35 induces intensive phosphorylation of Ser202/Thr205 of human tau. J Biol Chem. 2002 Nov 15;277(46):44525-30. Epub 2002 Sep 10. Erratum in: J Biol Chem 2003 Jan 10;278(2):1388. Abstract

    Li BS, Sun MK, Zhang L, Takahashi S, Ma W, Vinade L, Kulkarni AB, Brady RO, Pant HC. Regulation of NMDA receptors by cyclin-dependent kinase-5. Proc Natl Acad Sci U S A. 2001 Oct 23;98(22):12742-7. Epub 2001 Oct 02. Abstract

    Lu T, Pan Y, Kao SY, Li C, Kohane I, Chan J, Yankner BA. Gene regulation and DNA damage in the ageing human brain. Nature. 2004 Jun 24;429(6994):883-91. Epub 2004 Jun 09. Abstract

    Patrick GN, Zukerberg L, Nikolic M, de la Monte S, Dikkes P, Tsai LH. Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration.Nature. 1999 Dec 9;402(6762):615-22. Abstract

    Patzke H, Maddineni U, Ayala R, Morabito M, Volker J, Dikkes P, Ahlijanian MK, Tsai LH. Partial rescue of the p35-/- brain phenotype by low expression of a neuronal-specific enolase p25 transgene. J Neurosci. 2003 Apr 1;23(7):2769-78. Abstract

    Van den Haute C, Spittaels K, Van Dorpe J, Lasrado R, Vandezande K, Laenen I, Geerts H, Van Leuven F. Coexpression of human cdk5 and its activator p35 with human protein tau in neurons in brain of triple transgenic mice. Neurobiol Dis. 2001 Feb;8(1):32-44. Abstract