| |
 Senile
plaques and neurofibrillary tangles (NTs) are the two neuropathological
hallmarks of AD. The extended topographical distribution of NTs
provides a reliable pathological correlation to the degree of dementia,
the central symptom of AD. Ultrastructurally, NTs contain paired
helical filaments (PHFs). PHFs are composed of abnormally hyperphosphorylated
microtubule-associated tau protein. Carrying more phosphate than
it should makes tau unable to perform its normal function leading
to loss of tau function, cytoskeletal disruption, PHF formation,
and neurodegeneration.
There is no effective treatment for AD. The long-term goals
of Dr. Paudel’s laboratory are divided into two phases.
In the first phase they will elucidate the cellular and molecular
basis of neurofibrillary formation in AD brain. Based on the
acquired knowledge from the first phase, they will develop: 1,
diagnostic reagents for early AD detection; 2, develop therapeutic
approaches to slow or prevent NT formation; and 3, develop therapeutic
strategies to dissolve NT in neurons. Dr. Paudel has identified
several kinases and phosphatases that act upon tau in normal
and diseased brain. His laboratory has also found biological
molecules that influence tau phosphorylation and has delineated
several key cellular and biochemical steps that are involved
in the abnormal tau phosphorylation.
SOME RECENT PUBLICATIONS
1. |
Yuan, Z., Agarwal-Mawal, A. and Paudel, H. K. (2004).
14-3-3 binds and mediates phosphorylation of microtubule-associated
tau protein by Ser9 phosphorylated glycogen synthase kinase
3ß in the brain. J. Biol. Chem. 279, 26105-26114. MEDLINE link to this publication |
2. |
Agarwal-Mawal, A., Qureshi, H. Y., Cafferty, P. W.,
Yuan, Z., Han, D., Lin, R. and Paudel, H. K. (2003). 14-3-3
connects glycogen synthase kinase 3ß to tau within
a brain microtubule-associated tau phosphorylation complex.
J. Biol. Chem. 278, 12722-12728. MEDLINE link to this publication |
3. |
Sun, W., Qureshi, H. Y., Cafferty, P. W., Sobue, K.,
Agarwal-Mawal, A., Neufield, K. D. and Paudel, H. K. (2002)
Glycogen synthase kinase 3ß is complexed with tau
protein in brain microtubules. J. Biol. Chem. 277, 11933-11940. MEDLINE link to this publication |
4. |
Agarwal-Mawal, A. and Paudel, H. K. (2001) Neuronal
Cdc2-like protein kinase (Cdk5/p25) is associated with
protein phosphatase 1 and phosphorylates inhibitor-2. J.
Biol. Chem. 276, 23712-23718. MEDLINE link to this publication |
5. |
Sobue, K., Agarwal-Mawal, A., Wei, L., Sun, W, Miura,
Y., and Paudel, H. K. (2000) Interaction of Neuronal cdc2-like
protein kinase with microtubule-associated protein tau.
J. Biol. Chem. 275, 16673–16680. MEDLINE link to this publication |
6. |
Hashiguchi, M., Sobue, K., and Paudel, H. K. (2000)
14-3-3ζ
is
an effector of tau protein phosphorylation. J. Biol. Chem.
275, 25247–25254 MEDLINE link to this publication |
7. |
Hung, K. and Paudel, H. K. (2000). Ser67 phosphorylated
inhibitor 1 is a potent protein phosphatase 1 inhibitor.
Proc. Natl. Acad. Sci. (USA) 97, 5824-5829. MEDLINE link to this publication |
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