Deregulation of HDAC1 by p25/Cdk5 in neurotoxicity.
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.
Kim
Dohoon
D
Howard Hughes Medical Institute, Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Frank
Christopher L
CL
Dobbin
Matthew M
MM
Tsunemoto
Rachel K
RK
Tu
Weihong
W
Peng
Peter L
PL
Guan
Ji-Song
JS
Lee
Byung-Hoon
BH
Moy
Lily Y
LY
Giusti
Paola
P
Broodie
Nisha
N
Mazitschek
Ralph
R
Delalle
Ivanna
I
Haggarty
Stephen J
SJ
Neve
Rachael L
RL
Lu
Youming
Y
Tsai
Li-Huei
LH
D000818:Animals; D000831:Animals, Newborn; D002453:Cell Cycle / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D047369:Chromatin Immunoprecipitation / Q000379:methods; D000090266:Chromobox Protein Homolog 5; D020552:Comet Assay; D003213:Conditioning, Psychological / Q000502:physiology; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000502:physiology*; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage / Q000235:genetics; D005239:Fear / Q000502:physiology; D015870:Gene Expression / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D007511:Ischemia / Q000473:pathology; D019394:Ki-67 Antigen / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000201:enzymology* / Q000235:genetics; D009417:Nerve Tissue / Q000378:metabolism; D009474:Neurons / Q000502:physiology; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D016548:Prosencephalon / Q000378:metabolism; D051381:Rats; D014162:Transfection
C000715594:CBX5 protein, human; D019394:Ki-67 Antigen; D018809:Proliferating Cell Nuclear Antigen; D000090266:Chromobox Protein Homolog 5; D049452:Green Fluorescent Proteins; D051360:Cyclin-Dependent Kinase 5; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases