Journal
NATURE CELL BIOLOGY
Volume 12, Issue 6, Pages 563-U100Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncb2058
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Funding
- Parkinson Society Canada
- Heart and Stroke Foundation of Ontario
- Canadian Institutes of Health Research
- Parkinson's Disease Foundation
- Parkinson Research Consortium
- Brain Repair Program-Neuroscience Canada
- National Research Foundation, Ministry of Education, Science & Technology, South Korea [R31-2008-000-20009-0]
- National Research Foundation of Korea [R31-2008-000-20004-0] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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Accumulating evidence suggests that deregulated cyclin-dependent kinase 5 (Cdk5) plays a critical part in neuronal death. However, the pathogenic targets of Cdk5 are not fully defined. Here we demonstrate that the Cdk5 activator p35 interacts directly with apurinic/apyrimidinic endonuclease 1 (Ape1), a protein crucial for base excision repair (BER) following DNA damage. Cdk5 complexes phosphorylate Ape1 at Thr 232 and thereby reduces its apurinic/apyrimidinic (AP) endonuclease activity. Ape1 phosphorylation is dependent on Cdk5 in in vitro and in vivo. The reduced endonuclease activity of phosphorylated Ape1 results in accumulation of DNA damage and contributes to neuronal death. Overexpression of Ape1(WT) and Ape1(T232A), but not the phosphorylation mimic Ape1(T232E), protects neurons against MPP(+)/MPTP. Loss of Ape1 sensitizes neurons to death. Importantly, increased phosphorylated Ape1 was also observed in post-mortem brain tissue from patients with Parkinson's and Alzheimer's diseases, suggesting a potential link between Ape1 phosphorylation and the pathogenesis of neurodegenerative diseases.
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