Deregulation of HDAC1 by p25/Cdk5 in Neurotoxicity

    Authors

    D. Kim; C. L. Frank; M. M. Dobbin; R. K. Tsunemoto; W. Tu; P. L. Peng; J. S. Guan; B. H. Lee; L. Y. Moy; P. Giusti; N. Broodie; R. Mazitschek; I. Delalle; S. J. Haggarty; R. L. Neve; Y. Lu;L. H. Tsai

    Comments

    Authors: contact us about adding a copy of your work at STARS@ucf.edu

    Abstract

    Aberrant cell-cycle activity and DNA damage are emerging as important pathological components in various neurodegenerative conditions. However, their underlying mechanisms are poorly understood. Here, we show that deregulation of histone deacetylase 1 (HDAC1) activity by p25/Cdk5 induces aberrant cell-cycle activity and double-strand DNA breaks leading to neurotoxicity. In a transgenic model for neurodegeneration, p25/Cdk5 activity elicited cell-cycle activity and double-strand DNA breaks that preceded neuronal death. Inhibition of HDAC1 activity by p25/Cdk5 was identified as an underlying mechanism for these events, and HDAC1 gain of function provided potent protection against DNA damage and neurotoxicity in cultured neurons and an in vivo model for ischemia. Our findings outline a pathological signaling pathway illustrating the importance of maintaining HDAC1 activity in the adult neuron. This pathway constitutes a molecular link between aberrant cell-cycle activity and DNA damage and is a potential target for therapeutics against diseases and conditions involving neuronal death.

    Journal Title

    Neuron

    Volume

    60

    Issue/Number

    5

    Publication Date

    1-1-2008

    Document Type

    Article

    First Page

    803

    Last Page

    817

    WOS Identifier

    WOS:000261746700012

    ISSN

    0896-6273

    Share

    COinS