Cyclin-dependent kinase 5 is an upstream regulator of mitochondrial fission during neuronal apoptosis

Universitätsmedizin Göttingen, Göttingen, Lower Saxony, Germany
Cell Death and Differentiation (Impact Factor: 8.39). 05/2007; 14(4):651-61. DOI: 10.1038/sj.cdd.4402087
Source: PubMed

ABSTRACT Under physiological conditions, mitochondrial morphology dynamically shifts between a punctuate appearance and tubular networks. However, little is known about upstream signal transduction pathways that regulate mitochondrial morphology. We show that mitochondrial fission is a very early and kinetically invariant event during neuronal cell death, which causally contributes to cytochrome c release and neuronal apoptosis. Using a small molecule CDK5 inhibitor, as well as a dominant-negative CDK5 mutant and RNAi knockdown experiments, we identified CDK5 as an upstream signalling kinase that regulates mitochondrial fission during apoptosis of neurons. Vice versa, our study shows that mitochondrial fission is a modulator contributing to CDK5-mediated neurotoxicity. Thereby, we provide a link that allows integration of CDK5 into established neuronal apoptosis pathways.

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Available from: Gunnar P H Dietz, Aug 24, 2015
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    • "Activation of Cdk5 plays an early role in the cell death cascade before the initiation of mitochondrial dysfunction, and Cdk5 inhibition prevents the mitochondrial damage and cell death caused by Prx2 inactivationmediated oxidative stress (Sun et al. 2008). Interestingly, Cdk5 also regulates mitochondrial fission during neuronal apoptosis as an upstream signaling kinase (Meuer et al. 2007). However, the precise mechanism by which Cdk5 regulates mitochondrial morphology is still unclear. "
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    • "Cdk5 is one of the major kinases that hyperphosphorylates tau to create the forms present in the neurofibrillary tangles that are characteristic of AD and other neurodegenerative diseases, and Cdk5 hyperphosphorylates neurofilament to produce forms that are mislocalized to the cell soma in motor neuron disease (Lee and Tsai, 2003; Noble et al., 2003). Moreover, a mislocalized and deregulated form of Cdk5 is found associated with degenerating tissue in AD brains (Patrick et al., 1999), and the protein has been associated with many cellular pathologies that are linked to degeneration, including altered autophagy and mitochondrial disruption (Meuer et al., 2007; Qu et al., 2007; Furuya et al., 2010; Wong et al., 2011). Both increased and decreased Cdk5 activity causes cell death in vitro and in in vivo models (Jessberger et al., 2009; Zhang et al., 2010), and both are associated with neurodegeneration in animal models (Ohshima et al., 1996; Patrick et al., 1999; Takahashi et al., 2010). "
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    • "Cite this article as Cold Spring Harb Perspect Med 2012;4:a009332 In the context of PD, cell death induced by parkinsonian neurotoxins 6-OHDA, rotenone, and MPP þ in cultured neurons is associated with mitochondrial fragmentation (Barsoum et al. 2006; Meuer et al. 2007; Gomez-Lazaro et al. 2008). Supporting a pathogenic role for the latter, genetic inhibition of pro-fission Drp1 or overexpression of pro-fusion Mfn1 prevent cell death induced by these neurotoxins (Barsoum et al. 2006; Meuer et al. 2007; Gomez- Lazaro et al. 2008). Furthermore, pathogenic mutations in Parkin (an E3 ubiquitin ligase) and PINK1 (PTEN-induced putative kinase-1, a mitochondrially targeted kinase), which cause autosomal recessive forms of PD (Vila and Przedborski 2004), are associated with an increase in dysfunctional, fragmented mitochondria that can be rescued by pharmacological or genetic inactivation of Drp1 (Lutz et al. 2009; Cui et al. 2010). "
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