Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models

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Homo sapiens
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Post-mitotic neurons do not have an active cell cycle. However, deregulation of Cyclin Dependent Kinase-5 (CDK5) activity in these neurons can aberrantly activate various components of cell cycle leading to neuronal death (Chang et al. 2012). Random activation of cell cycle proteins has been shown to play a key role in the pathogenesis of several neurodegenerative disorders (Yang et al. 2003, Lopes et al. 2009). CDK5 is not activated by the canonical cyclins, but binds to its own specific partners, CDK5R1 and CDK5R2 (aka p35 and p39, respectively) (Tsai et al. 1994, Tang et al. 1995). Expression of p35 is nearly ubiquitous, whereas p39 is largely expressed in the central nervous system. A variety of neurotoxic insults such as beta-amyloid (A-beta), ischemia, excitotoxicity and oxidative stress disrupt the intracellular calcium homeostasis in neurons, thereby leading to the activation of calpain, which cleaves p35 into p25 and p10 (Lee et al. 2000). p25 has a six-fold longer half-life compared to p35 and lacks the membrane anchoring signal, which results in its constitutive activation and mislocalization of the CDK5:p25 complex to the cytoplasm and the nucleus. There, CDK5:p25 is able to access and phosphorylate a variety of atypical targets, triggering a cascade of neurotoxic pathways that culminate in neuronal death. One such neurotoxic pathway involves CDK5-mediated random activation of cell cycle proteins which culminate in neuronal death. Exposure of primary cortical neurons to oligomeric beta-amyloid (1-42) hyper-activates CDK5 due to p25 formation, which in turn phosphorylates CDC25A, CDC25B and CDC25C. CDK5 phosphorylates CDC25A at S40, S116 and S261; CDC25B at S50, T69, S160, S321 and S470; and CDC25C at T48, T67, S122, T130, S168 and S214. CDK5-mediated phosphorylation of CDC25A, CDC25B and CDC25C not only increases their phosphatase activities but also facilitates their release from 14-3-3 inhibitory binding. CDC25A, CDC25B and CDC25C in turn activate CDK1, CDK2 and CDK4 kinases causing neuronal death. Consistent with this mechanism, higher CDC25A, CDC25B and CDC25C activities were observed in human Alzheimer's disease (AD) clinical samples, as compared to age-matched controls. Inhibition of CDC25 isoforms confers neuroprotection to beta-amyloid toxicity, which underscores the contribution of this pathway to AD pathogenesis

Literature References
PubMed ID Title Journal Year
22899714 Deregulated Cdk5 triggers aberrant activation of cell cycle kinases and phosphatases inducing neuronal death

Chang, KH, Vincent, F, Shah, K

J. Cell. Sci. 2012
8090221 p35 is a neural-specific regulatory subunit of cyclin-dependent kinase 5

Chae, T, Caviness, VS, Harlow, E, Delalle, I, Tsai, LH

Nature 1994
7592934 An isoform of the neuronal cyclin-dependent kinase 5 (Cdk5) activator

Yeung, J, Matsushita, M, Tang, D, Matsui, H, Lee, KY, Wang, JH, Tomizawa, K, Hatase, O

J. Biol. Chem. 1995
12684440 Neuronal cell death is preceded by cell cycle events at all stages of Alzheimer's disease

Yang, Y, Mufson, EJ, Herrup, K

J. Neurosci. 2003
10830966 Neurotoxicity induces cleavage of p35 to p25 by calpain

Peng, J, Kwon, YT, Friedlander, RM, Lee, MS, Li, M, Tsai, LH

Nature 2000
19519302 Cell cycle re-entry in Alzheimer's disease: a major neuropathological characteristic?

Lopes, JP, Oliveira, CR, Agostinho, P

Curr Alzheimer Res 2009
Name Identifier Synonyms
Alzheimer's disease DOID:10652 AD, Alzheimers dementia, Alzheimer disease
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