Abl deregulates Cdk5 kinase activity and subcellular localization in Drosophila neurodegeneration

Abstract

Although Abl functions in mature neurons, work to date has not addressed Abl's role on Cdk5 in neurodegeneration. We found that b-amyloid (Ab42) initiated Abl kinase activity and that blockade of Abl kinase rescued both Drosophila and mammalian neuronal cells from cell death. We also found activated Abl kinase to be necessary for the binding, activation, and translocalization of Cdk5 in Drosophila neuronal cells. Conversion of p35 into p25 was not observed in Ab42-triggered Drosophila neurodegeneration, suggesting that Cdk5 activation and protein translocalization can be p25-independent. Our genetic studies also showed that abl mutations repressed Ab42-induced Cdk5 activity and neurodegeneration in Drosophila eyes. Although Ab42 induced conversion of p35 to p25 in mammalian cells, it did not sufficiently induce Cdk5 activation when c-Abl kinase activity was suppressed. Therefore, we propose that Abl and p35/p25 cooperate in promoting Cdk5-pY15, which deregulates Cdk5 activity and subcellular localization in Ab42-triggered neurodegeneration. Alzheimer's disease (AD), the most frequently diagnosed neurodegenerative disease, is characterized histologically by two hallmark features: senile plaques, which are extracellular deposits of b-amyloid(Ab42), and intracellular neurofibrillary tangles of aggregated hyperphosphorylated tau protein.1 The accumulation of Ab42 has been found to precede the pathological neurodegenerational changes, 2 and the inhibition of Ab42 accumulation by amyloid vaccination can effectively prevent the pathogenesis in mammalian AD animals.3 Less clear is the downstream protein targets of Ab42 toxicity in neurons. Thus, study of the Ab42-induced signaling cascade is of interest because it may provide clues for designing therapeutic strategies for the treatment of AD. AD brain samples show elevated cdk5 activity, 4 and deregulated Cdk5 has been associated with the tau hyperphosphorylation, a state leading to AD.5 Like other Cdk members, Cdk5 needs to bind with its regulatory partners to activate kinase activity. One of Cdk5's activating partners, p35, is expressed primarily in postmitotic neurons.6 Cdk5 also appears to be deregulated by its association with p25, a calpain digestion product of p35 in AD neurons. 7 The Cdk5/ p25 complex is thought to hyperphosphorylate tau and reduce tau's association with microtubules, resulting in neuronal apoptosis.8 Recently, c-Abl has been reported to phosphorylate and activate Cdk5 through the adaptor protein Cables during brain development. 9 The integration of Abl and Cdk5 into the same biological pathway suggests they have similar roles in neuronal cytoskeletal regulation and axon guidance.The Abl kinase, apparently evolutionarily conserved from flies to humans, is involved in the development of the nervous system. 10 Based on genetic studies of mice 11 and Drosophila, 12 abl mutations may lead to neuronal defects. Abl kinase has also been implicated in the regulation of apoptosis. 13Interestingly, the cytotoxicity of Ab42 is considered a crucial stress f...

Regulation of Androgen Receptor and Prostate Cancer Growth by Cyclin-dependent Kinase 5

“…In addition, the interactions between Cdk5 and AR in prostate cancer cells were correlated to the status of Cdk5 activation (Fig. 1B), which was in accordance with our previous studies on Abl kinase (12) in which the interaction between kinase and substrate was determined by kinase activity.…”

“…Lysates were analyzed by direct immunoblotting (20 -35 g/lane) or blotting after immunoprecipitation (0.5-1 mg/immunoprecipitation) using methods modified from those previously described (12,21,23,24). Immunoprecipitates were collected by binding to 25-40 l of the ExactaCruz beads (Santa Cruz).…”

“…The crucial role of the Cdk5-p35 complex is to support the development of the central nervous system (CNS) (10,11). Our previous report shows the importance of Cdk5 in a Drosophila neurodegenerative model (12). In addition to its roles in CNS, numerous groups have sequentially demonstrated the involvement of Cdk5 in different cancers, including liver cancer (13), colorectal cancer (14), pancreatic cancer (15), breast cancer (16,17), and lung cancer (18 -20).…”

Dopaminergic and Glutamatergic Signaling Crosstalk in Huntington's Disease Neurodegeneration: The Role of p25/Cyclin-Dependent Kinase 5

“…Increased intracellular calcium in turn leads to higher calpain activity that results in enhanced cleavage of p35 into p25 (Lee et al, 2000). In addition, as our data demonstrate, activation of NMDAR may potentiate D 1 R-mediated phosphorylation of Cdk5 at Tyr 15 , which has been shown to regulate Cdk5-induced neurotoxicity (Lin et al, 2007). The generation of p-Cdk5/p25 complexes implies Cdk5 hyperactivation that is responsible for the phosphorylation of new substrates such as tau protein.…”

“…We have examined two important features of Cdk5 activation related to its pro-apoptotic function: the levels of Tyr 15 phosphorylation (Lin et al, 2007) and the accumulation of p25 as a result of calpain-mediated p35 cleavage (Kusakawa et al, 2000;Lee et al, 2000). Our results in knock-in striatal cells define a new role of mutant huntingtin as modulator of the Cdk5 pathway by (1) decreasing Cdk5 expression and increasing the levels of phosphorylated Tyr 15 -Cdk5 and (2) by increasing the conversion of p35 into p25, which in turn results in enhanced Cdk5 activity.…”