Harish C Pant
National Institutes of Health, USA
Posters & Accepted Abstracts: J Neurol Neurophysiol
Cdk5 is a member of cyclin-dependent kinases. It is unique among Cdk family of kinases; it is not activated by cyclins but is activated exclusively by the brain-specific p35/p25/p67 proteins. It is a multifunctional protein kinase constitutively active in nervous tissues. It is implicated in ameliorating various neurodegenerative diseases phenotypes including AD. Cdk5, (Cdk5/p35), activity is tightly regulated and essential for nervous system development and neuronal functions. Emerging evidence suggests that its deregulation and hyper activation due to neuronal insults produced p25 and accumulation and aggregation of synaptic and cytoskeletal proteins in neuronal cells forming early stages of neurofibrillary tangles, plaques, Lewy bodies inclusions. These aggregated proteins and peptides are the hallmarks of AD, PD and ALS pathologies. On the basis of a large number of studies we have proposed Cdk5/p35 is a physiological and Cdk5/p25 is pathological target. To reduce the pathological phenotypes in situ / in vivo we discovered p5, a 24-amino acid truncated peptide from Cdk5 activator protein, p35, selectively inhibited the deregulated and hyperactive active Cdk5, (Cdk5/p25), induces pathology, but not Cdk5, (Cdk5/p35), kinase essential for nervous system development, function and survival. Recently it has been provided sufficient information that a modified truncated 24-amino acid peptide (TFP5), derived from the Cdk5 activator p35, penetrates the blood-brain barrier upon intraperitoneal injections (i.p.), inhibits significantly abnormal Cdk5 hyperactivity, and rescues significantly, AD pathology (up to 70�80%) in 5XFAD, p25Tg AD model and MPTP (mitochondrial toxin) induced phenotypes in Parkinson�s disease model mice. The present talk will provide the molecular and cellular basis of the selectivity of these two forms of kinases, Cdk5/p35 and Cdk5/p25, physiological and pathological behavior of Cdk5/p35 and Cdk5/p25 kinases. We propose TFP5 may be able to ameliorate a number of phenotypes in different neurodegenerative disease. panth@ninds.nih.gov
