|
|
Ronald K. Liem, Ph.D.
Professor of Pathology and Anatomy & Cell Biology
|
Research
Summary
Neuronal cytoskeleton and neurdegenerative disease.
Overexpression and mutations of the neuronal intermediate filament proteins leads to neuronal degeneration, showing that malfunctions in neuronal intermediate filaments can be responsible for neurodegenerative diseases. We have focused on (-internexin, a neuronal intermediate filament protein, which is expressed in neurons immediately after they start to differentiate. We have found that overexpression of this protein leads to axonal swellings and degeneration in the CNS. We are interested in delineating the mechanism by which this apparent block in transport of filaments occurs and how this leads to degeneration and neuronal cell death.
The diversity of neuronal intermediate filaments in different areas of the nervous system, point to the possibility that each of these proteins interacts specifically with other components of the cytoskeleton. Interactions between neuronal cytoskeletal elements have been shown by the identification of a neuronal form of dystonin, which has both an intermediate filament binding domain and an actin binding domain. Mutations in dystonin in mice result in severe sensory neuron defects. We have shown that dystonin specifically interacts with the neuronal intermediate filament protein, peripherin, which is found predominantly in sensory neurons. We have characterized another member of this family of proteins, ACF7, which has sequence similarities to both dystonin and dystrophin. Mutations in this protein might also lead to degeneration. We expect that other related proteins are likely to be present in the nervous system that may cross-link neuronal intermediate filament proteins with other cytoskeletal elements.
One of the hallmarks of Alzheimer's Disease is the presence of paired helical filaments, which are composed of the microtubule associated protein, tau. Abnormal tau phosphorylation has been shown to be occur in Alzheimer's Disease. Recent studies have identified mutations in tau in a hereditary neurodegenerative disease, frontal temporal dementia with Parkinsonisn. We are determining how these mutations might destabilize microtubules in vitro and in vivo and whether these mutations would lead to the likelihood that tau is abnormally phosphorylated. By using transgenic models, we hope to determine how these mutations might lead to neurodegeration.
http://www.cumc.columbia.edu/dept/gsas/anatomy/Faculty/Liem/
|
|
|
|
|
|
|
|
|
top
|
