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Journal of Public Health Policy and Planning | Volume 3
April 08-09, 2019 | Zurich, Switzerland
Health Care and Neuroscience
International Conference on
Neuroprotective and Restorative roles of a small peptide derived from Neuronal
cell cycle like kinase (Cdk5) activator protein (p35)
Harish C Pant
National Institutes of Health, USA
C
dk5 is a member of cyclin-dependent kinases.
It is unique among cell cycle kinases. It is not
activated by cyclins but is regulated exclusively
by the brain-specific Cdk5 activator protein
of MW p35 kDa and p39 kDa. We have found
that a small 24 amino acid truncated peptide
derived from p35 implicated in ameliorating
various neurodegenerative diseases phenotypes
including AD. Cdk5 is a multifunctional protein
kinase, essential for nervous system development,
function and survival. The heterodimeric, (Cdk5/
p35), activity is tightly regulated due to its N-
terminus myristoylated head domain anchoring
to the membrane, localized to plasma membrane
and membranous structures. Now emerging
evidence suggest that upon neuronal insults,
calcium entry activates calpain produces cleaved
p25 kDa protein, which has higher affinity for Cdk5
induces its deregulation and hyperactivation of
Cdk5 (Cdk5/p25). Hyperactivity (Cdk5/p25) induces
accumulation of hyperphosphorylated cytoskeletal
proteins including tau and neurofilament. The
aggregation of these neuronal proteins in neuronal
cell bodies are highly toxic and are the early stages
of neurofibrillary tangles, plaques, Lewy bodies
inclusions. These aggregated proteins and peptides
are the hallmarks of AD, PD and ALS pathologies.
We have proposed Cdk5/p35 is a physiological
and Cdk5/p25 is the pathological target. We have
discovered p5 a truncated 24 amino acid peptide
derivedfromp35selectivelyinhibitsthederegulated
and hyperactive active (Cdk5/p25) kinase, produced
due to neuronal insults, induces pathology but
not the Cdk5/p35, essential for nervous system
development, function and survival. Recently our
laboratory has provided sufficient information
that a modified truncated 24-amino acid peptide
(TFP5), derived from the Cdk5 activator p35/p25,
penetrates and crosses blood-brain barrier upon
intraperitoneal injection (i.p), inhibits abnormal
Cdk5 hyperactivity, and prevents, AD pathology
in 5XFAD and p25Tg AD model mice. In addition,
TFP5 treatment also rescues MPTP, a mitochondrial
toxin induced Parkinson’s disease model mice.
The present talk will provide the molecular and
cellular mechanisms of the selectivity of these Tp5/
TFP5 peptides two forms of the kinases, Cdk5/p35
and Cdk5/p25. We propose Tp5/TFP5 can act as a
therapeutic reagent for neurological diseases.
e
:
panth@ninds.nih.gov