Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration

@article{Patrick1999ConversionOP,
  title={Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration},
  author={Gentry N Patrick and Lawrence R. Zukerberg and Margareta Nikoli{\'c} and Suzanne de la Monte and Pieter Dikkes and Li-Huei Tsai},
  journal={Nature},
  year={1999},
  volume={402},
  pages={615-622}
}
Cyclin-dependent kinase 5 (Cdk5) is required for proper development of the mammalian central nervous system. To be activated, Cdk5 has to associate with its regulatory subunit, p35. We have found that p25, a truncated form of p35, accumulates in neurons in the brains of patients with Alzheimer's disease. This accumulation correlates with an increase in Cdk5 kinase activity. Unlike p35, p25 is not readily degraded, and binding of p25 to Cdk5 constitutively activates Cdk5, changes its cellular… 
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TLDR
Elevated Cdk5 activity in mice exhibiting tau hyperphosphorylation, and in AD brains are shown, and the molecular mechanisms whereby Cdk4 activity is upregulated in AD brain remain to be investigated.
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TLDR
It is demonstrated that Pctaire1 interacts with p35, both in vitro and in vivo, and that phosphorylation of Pctaires1 by Cdk5 enhances its kinase activity.
Neurotoxicity induces cleavage of p35 to p25 by calpain
TLDR
Observations indicate that cleavage of p35 to p25 by calpain may be involved in the pathogenesis of Alzheimer's disease.
Cdk5: Multitasking between physiological and pathological conditions
Identification of p10 as a neurotoxic product generated from the proteolytic cleavage of the neuronal Cdk5 activator
TLDR
It is demonstrated for the first time that p10‐mediated apoptosis occurred via a caspases‐independent pathway and novel results present that the accumulation of p10 to the detergent‐insoluble fraction may be a crucial pathological event to triggering neuronal cell death.
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