title: Identification of p10 as a neurotoxic product generated from the proteolytic cleavage of the neuronal Cdk5 activator.
abstract: 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.
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 8 Medical Drive, Singapore 117597, Singapore.
authors.forename: Jenny
authors.initials: J
authors.lastname: Chew
authors.forename: Minghui Jessica
authors.initials: MJ
authors.lastname: Chen
authors.forename: Alan Yiu-Wah
authors.initials: AY
authors.lastname: Lee
authors.forename: Zhao Feng
authors.initials: ZF
authors.lastname: Peng
authors.forename: Kevin Wai Yin
authors.initials: KW
authors.lastname: Chong
authors.forename: Lisheng
authors.initials: L
authors.lastname: He
authors.forename: Boon Huat
authors.initials: BH
authors.lastname: Bay
authors.forename: Jian Ming Jeremy
authors.initials: JM
authors.lastname: Ng
authors.forename: Robert Z
authors.initials: RZ
authors.lastname: Qi
authors.forename: Nam Sang
authors.initials: NS
authors.lastname: Cheung
mesh_terms: 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
chemical_list: C556901:Cdk5 activator fragment p10, mouse; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; C089495:neuronal Cdk5 activator (p25-p35); D010447:Peptide Hydrolases; D020169:Caspases