Identification of p10 as a neurotoxic product generated from the proteolytic cleavage of the neuronal Cdk5 activator.
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.
Chew
Jenny
J
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 8 Medical Drive, Singapore 117597, Singapore.
Chen
Minghui Jessica
MJ
Lee
Alan Yiu-Wah
AY
Peng
Zhao Feng
ZF
Chong
Kevin Wai Yin
KW
He
Lisheng
L
Bay
Boon Huat
BH
Ng
Jian Ming Jeremy
JM
Qi
Robert Z
RZ
Cheung
Nam Sang
NS
D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D006868:Hydrolysis; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism* / Q000502:physiology*; D019636:Neurodegenerative Diseases / Q000209:etiology* / Q000473:pathology; D009474:Neurons / Q000166:cytology*; D010446:Peptide Fragments / Q000032:analysis / Q000502:physiology*; D010447:Peptide Hydrolases
C556901:Cdk5 activator fragment p10, mouse; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; C089495:neuronal Cdk5 activator (p25-p35); D010447:Peptide Hydrolases; D020169:Caspases