Targeting Cdk5 activity in neuronal degeneration and regeneration.
The major priming event in neurodegeneration is loss of neurons. Loss of neurons by apoptotic mechanisms is a theme for studies focused on determining therapeutic strategies. Neurons following an insult, activate a number of signal transduction pathways, of which, kinases are the leading members. Cyclin-dependent kinase 5 (Cdk5) is one of the kinases that have been linked to neurodegeneration. Cdk5 along with its principal activator p35 is involved in multiple cellular functions ranging from neuronal differentiation and migration to synaptic transmission. However, during neurotoxic stress, intracellular rise in Ca(2+) activates calpain, which cleaves p35 to generate p25. The long half-life of Cdk5/p25 results in a hyperactive, aberrant Cdk5 that hyperphosphorylates Tau, neurofilament and other cytoskeletal proteins. These hyperphosphorylated cytoskeletal proteins set the groundwork to forming neurofibrillary tangles and aggregates of phosphorylated proteins, hallmarks of neurodegenerative diseases like Alzheimer's disease, Parkinson's disease and Amyotropic Lateral Sclerosis. Attempts to selectively target Cdk5/p25 activity without affecting Cdk5/p35 have been largely unsuccessful. A polypeptide inhibitor, CIP (Cdk5 inhibitory peptide), developed in our laboratory, successfully inhibits Cdk5/p25 activity in vitro, in cultured primary neurons, and is currently undergoing validation tests in mouse models of neurodegeneration. Here, we discuss the therapeutic potential of CIP in regenerating neurons that are exposed to neurodegenerative stimuli.
Kanungo
Jyotshnabala
J
Laboratory of Neurochemistry, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA.
Zheng
Ya-li
YL
Amin
Niranjana D
ND
Pant
Harish C
HC
D000818:Animals; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D020536:Enzyme Activators / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D051379:Mice; D009410:Nerve Degeneration / Q000201:enzymology*; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology*; D010455:Peptides / Q000494:pharmacology
D020536:Enzyme Activators; D010455:Peptides; D051360:Cyclin-Dependent Kinase 5