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he Biology of Neurodegeneration program evolved in our laboratory studying the basic biology of neuronal
cytoskeletal protein phosphorylation regulation during development and normal function in the adult.
To understand the molecular basis of neurodegeneration our major focus has been to study the regulation of
compartment-specific patterns of cytoskeletal protein phosphorylation in neuronal perikarya and axons. We
have demonstrated that phosphorylation of the numerous acceptor sites on neuronal intermediate filament
proteins (NIFPs) as neurofilaments (NFs) was tightly regulated topographically and generally confined to the
axonal compartment. It was recognized that in neurodegenerative disorders such as Alzheimer?s disease (AD) and
Amyotrophic lateral sclerosis (ALS), the pathology was characterized by an accumulation of aberrantly and hyper-
phosphorylated cytoskeletal proteins in cell bodies, suggesting that topographic regulation had been compromised.
This led the discovery of neuronal cyclin dependent kinase 5 (Cdk5). Our studies of neurodegeneration in cell
culture and model mice with emphasis on specific neuronal protein kinases, (Cdk5), that targets numerous
neuronal proteins including cytoskeletal proteins, which when deregulated, may be responsible for the pathology
seen in neurodegeneration. In cell systems, neuronal stress leads to deregulated kinases, for example, deregulation
of Cdk5, accompanied by abnormal cytoskeletal protein phosphorylation and cell death characteristic of
neurodegeneration. Recently we have developed peptides derived from, p35, a neuron specific activator of Cdk5,
for deregulated Cdk5 activity which rescue cells
from this stress induced pathology and
, in AD
model mice. We have investigated (1) how cytoskeletal protein phosphorylation is topographically and tightly
regulated in neurons? (2) What factors are responsible for this deregulation? and (3) treated mouse models of AD
therapeutically with peptide that specifically inhibit deregulated Cdk5.
Harish C. Pant supervises and manages a research program dedicated to understanding the mechanisms regulating neuronal
cytoskeletal phosphorylation in health and disease. For several years our focus has been on the role of the multifunctional neuronal
kinase complex Cdk5/p35, in neuronal cytoskeleton phosphorylation, neuronal development, synapogenesis, and survival.
Within the past few years, however, we, and other laboratories, have shown that Cdk5 is abnormally hyperactivated as a Cdk5/
p25 complex in several neurodegenerative disorders which correlates with their specific brain pathologies. Serendipitously, we
identified a small peptide (p5) derived from the cdk5 activator, p35, that specifically inhibited the abnormally activated Cdk5 without
affecting the normal endogenous kinase. Accordingly, current and future studies are designed to (1) determine whether this peptide
acts therapeutically in rescuing neurodegenerative model mice sharing the hyperactivated Cdk5-induced phenotypes of Alzheimer
Disease (AD), Amyotrophic Sclerosis (ALS), Parkinson?s disease (PD) and HIV-dementia. (2) if so, what is its mechanism of action
in each case? And, ultimately, (3) does it qualify as a possible candidate for human therapy?
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