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Identification of p10 as a Neurotoxic Product Generated From the Proteolytic Cleavage of the Neuronal Cdk5 Activator


Chew, J and Chen, Minghui Jessica and Lee, AYW and Peng, ZF and Chong, KWY and He, LS and Bay, BH and Ng, JMJ and Qi, RZ and Cheung, NS, Identification of p10 as a Neurotoxic Product Generated From the Proteolytic Cleavage of the Neuronal Cdk5 Activator, Journal of Cellular Biochemistry, 111, (5) pp. 1359-1366. ISSN 0730-2312 (2010) [Refereed Article]

DOI: doi:10.1002/jcb.22864


The involvement of cyclin-dependent kinase-5 (Cdk5) and p25, the proteolytic fragment of activator p35, has long been implicated in the development of neuron-fibrillary tangles (NFTs), a hallmark of Alzheimer's disease (AD). Findings in this area over the past decade have been highly controversial and inconclusive. Here we report unprecedented detection of endogenous p10, the smaller proteolytic fragment of the Cdk5 activator p35 in treated primary cortical neurons that underwent significant apoptosis, triggered by proteasome inhibitors MG132 and lactacystin, and protein kinase inhibitor staurosporine (STS). p10 appeared exclusively in the detergent-resistant fraction made up of nuclear matrix, membrane-bound organelles, insoluble membrane proteins, and cytoskeletal components. Intriguingly, transient overexpression of p10 in neural cells induced apoptotic morphologies, suggesting that p10 may play an important role in mediating neuronal cell death in neurodegenerative diseases. We demonstrated for the first time that p10-mediated apoptosis occurred via a caspases-independent pathway. Furthermore, as p10 may contain the myristoylation signal for p35 which is responsible for binding p35 to several intracellular components and the membrane, all in all these novel results present that the accumulation of p10 to the detergent-insoluble fraction may be a crucial pathological event to triggering neuronal cell death.

Item Details

Item Type:Refereed Article
Research Division:Biomedical and Clinical Sciences
Research Group:Neurosciences
Research Field:Neurology and neuromuscular diseases
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Chen, Minghui Jessica (Ms Minghui Chen)
UTAS Author:Cheung, NS (Dr Nam Cheung)
ID Code:70499
Year Published:2010
Web of Science® Times Cited:5
Deposited By:Research Division
Deposited On:2011-06-23
Last Modified:2011-06-23

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