Associate Professor, Department of Neurology and Neurosurgery,
Major Research Activities
Dr. Paudel's research focuses on the molecular mechanisms of Alzheimer's and Parkinson's diseases.
Alzheimer’s disease (AD) is the most common cause of dementia among the elderly. The neuropathological features of AD are progressive neuronal and synaptic loss in brain regions associated with cognitive dysfunction and the deposition of two defining pathological hallmarks, senile plaques (SPs) and neurofibrillary tangles (NFTs). The topographical distribution of NFTs in AD brains correlate with the degree of dementia and the clinical expression of the disease. Reducing and/or preventing NFT formation is one of the major therapeutic strategies against AD. NFTs are composed mainly of paired helical filaments (PHFs). Microtubule-associated protein tau is the major constituent of PHFs. Tau isolated from PHFs is abnormally hyperphosphorylated. In AD brains, tau hyperphosphorylation prevents tau from binding to microtubules, resulting in microtubule instability and neurodegeneration. Filamentous tau is also observed in a group of neurological disorders that include frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17), corticobasal degeneration, progressive supranuclear palsy, and Pick's disease. In all these disorders, tau filaments similar to PHFs are observed. Supporting the idea that tau is a key component in PHFs and disease pathology, tau gene mutations associated with familial FTDP-17 enhance tau hyperphosphorylation and tau fibrillization in vitro and in vivo. The primary focus of Dr. Paudel's laboratory is to elucidate the molecular mechanism by which tau is hyperphosphorylated, leading to the formation of PHFs and neurodegeneration in AD brains.
Parkinson’s disease (PD) is a common, chronic, neurodegenerative disease of the central nervous system characterized by movement disorder manifesting as bradykinesia, rigidity, and tremor. Neuropathological evaluations reveal substantial loss of dopaminergic neurons in the substantia nigra pars compacta and the presence of insoluble cytoplasmic inclusions known as Lewy bodies, which contain aggregated proteins. The main component of Lewy bodies is a small neuronal-specific protein: α-synuclein. Genetic studies have identified missense mutations (A30P, A53P and E46K) in the α-synuclein gene. In addition, duplication and triplication of the α-synuclein gene are associated with the familial form of PD. Studies indicate that α-synuclein contributes to neurotoxicity in a host of human neurodegenerative disorders, referred to collectively as synucleinopathies. In vitro studies have shown that recombinant α-synuclein can aggregate to form amyloid fibrils that resemble Lewy bodies, and that α-synuclein promotes Lewy body-like inclusion formation in neural tissue. Another focus of his laboratory is to elucidate the molecular mechanism by which α-synuclein fibrillizes and forms Lewy bodies in the brain.
Lu, Y. Li, T., Qureshi, HY, Han D. and Paudel, HK (2011) Early growth response 1 (Egr-1) regulates phosphorylation of microtubule-associated protein tau in mammalian brain J. Biol. Chem. 286, 20569- 20581Qureshi, H. Y and Paudel, H. K. (2011) Parkinsonian neurotoxin MPTP and α-synuclein mutations promote tau protein phosphorylation at Ser262 and destabilize microtubule cyrtoskeleton in vitro (2011). J. Biol. Chem. 286, 5055-5068.Han, D., Qureshi, H., Lu, Y. and Paudel, H. K. (2009) Familial FTDP-17 missense mutations inhibit microtubule assembly promoting activity of tau by increasing phosphorylation at Ser202 in vitro. J. Biol. Chem. 284, 13422-134331.