Cyclin-Dependent Kinase 5 Is Essential for Neuronal Cell Cycle Arrest and Differentiation

Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 11/2005; 25(42):9658-68. DOI: 10.1523/JNEUROSCI.1773-05.2005
Source: PubMed


Cyclin-dependent kinase 5 (Cdk5) is a serine/threonine kinase with significant homology to cell cycle-related Cdks but is not believed to be active in a typical cell cycle. In Cdk5-deficient embryos and Cdk5 chimeras, migration and survival of postmitotic neurons is compromised in a cell-autonomous manner. In the present study, we show that loss of Cdk5 leads to both failure of neuronal differentiation and loss of cell cycle control. Using specific cytoskeletal proteins as indices of neuronal differentiation, we find that Cdk5-deficient neurons are significantly arrested or delayed in their developmental program both in vivo and in vitro. For example, immunocytochemistry of embryonic day 16 (E16) cortex reveals that the expression of microtubule-associated protein 2c (Map-2c), a marker of mature neurons, is nearly absent in Cdk5(-/-) cells that have migrated to the cortical plate while these same cells continue to express nestin. Similarly, in vitro, Map-2-positive cells are rare in cultures from E16 Cdk5(-/-) embryos. Cell cycle control is also deficient in Cdk5(-/-) cells. In vivo, neurons engaged in cell cycle activities are found in the cortical plate, and, in vitro, class III beta-tubulin-positive cells continue to label with bromodeoxyuridine even after 5 d of incubation. Transfection of a wild-type Cdk5 construct reveals that cell cycle control can be regained in Cdk5(-/-) cells by overexpression of Cdk5. These data indicate that Cdk5 is necessary for both neuronal differentiation and cell cycle inhibition.

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    • "In particular, although Cdk5 is normally located in both nucleus and cytoplasm [131] [132] [133] [134] [135], the loss of nuclear Cdk5 leads to a failure of cell cycle suppression both in vivo and in vitro. Cell cycle activity detected in Cdk5-/-neurons includes the abnormal expression of cell cycle proteins such as cyclin D, cyclin A, and PCNA as well as 5-bromo-2-deoxyuridine incorporation [130]. Similar cell cycle events are found in neurons at risk for death in AD [43] [136]. "
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    ABSTRACT: Early-onset familial Alzheimer's disease (EOFAD) and late-onset sporadic AD (LOSAD) both follow a similar pathological and biochemical course that includes: neuron and synapse loss and dysfunction, microvascular damage, microgliosis, extracellular amyloid-β deposition, tau phosphorylation, formation of intracellular neurofibrillary tangles, endoreduplication and related cell cycle events in affected brain regions. Any mechanistic explanation of AD must accommodate these biochemical and neuropathological features for both forms of the disease. In this insight paper we provide a unifying hypothesis for EOFAD and LOSAD that proposes that the aberrant re-entry of terminally differentiated, post-mitotic neurons into the cell division cycle is a common pathway that explains both early and late-onset forms of AD. Cell cycle abnormalities appear very early in the disease process, prior to the appearance of plaques and tangles, and explain the biochemical (e.g. tau phosphorylation), neuropathological (e.g. neuron hypertrophy; polypoidy) and cognitive changes observed in EOFAD and LOSAD. Genetic mutations in AβPP, PSEN1, and PSEN2 that alter amyloid-β precursor protein and Notch processing drive reactivation of the cell cycle in EOFAD, while age-related reproductive endocrine dyscrasia that upregulates mitogenic TNF signaling and AβPP processing toward the amyloidogenic pathway drives reactivation of the cell cycle in LOSAD. In essence, AβPP and presenilin mutations initiate early, what endocrine dyscrasia initiates later: aberrant cell cycle re-entry of post-mitotic neurons leading to neurodegeneration and cognitive decline in AD. Inhibition of cell cycle re-entry in post-mitotic neurons may be a useful therapeutic strategy to prevent, slow or halt disease progression.
    Full-text · Article · Jul 2015 · Journal of Alzheimer's disease: JAD
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    • "CDK5 phosphorylates NFs directly and also phosphorylates MT-associated proteins such as MAP2, MAP1b, and Tau, which induces the formation and stability of MTs when phosphorylated. CDK5 also regulates the NUDEL protein, which is associated with dynein motor activity (Ohshima et al., 1996; Niethammer et al., 2000; Cicero and Herrup, 2005; Zheng et al., 2007). "
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    Full-text · Article · Sep 2014 · Frontiers in Aging Neuroscience
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    • "A common consequence of targeted cancer therapeutics in rapidly dividing bulk tumor cells is the ability of a compound to arrest cell division, usually leading to either differentiation or apoptosis. Interestingly, in the case of neurodegenerative pathways associated with CDK5 activation, there is often transient reactivation of cell cycle machinery directly preceding neuronal cell death (Cicero et al., 2005). Therefore, anticancer compounds that modulate the cell cycle may be active even in typically nondividing cells of the brain, and furthermore the differentiation-promoting effects may support production of mature neuronal progeny from endogenous regions of neurogenesis. "
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