Title

Deregulation Of Hdac1 By P25/Cdk5 In Neurotoxicity

Keywords

HUMDISEASE; MOLNEURO; SIGNALING

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. © 2008 Elsevier Inc. All rights reserved.

Publication Date

12-10-2008

Publication Title

Neuron

Volume

60

Issue

5

Number of Pages

803-817

Document Type

Article

Personal Identifier

scopus

DOI Link

https://doi.org/10.1016/j.neuron.2008.10.015

Socpus ID

57049177826 (Scopus)

Source API URL

https://api.elsevier.com/content/abstract/scopus_id/57049177826

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