Ronald Liem, Ph.D.
Cellular and molecular studies of the neuronal cytoskeleton
Our laboratory studies the neuronal cytoskeleton and its relationship to neurodegenerative diseases. In the mammalian nervous system a variety of neuronal intermediate filament proteins are expressed. 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. Recent studies have shown that neurofilaments are mutated in Charcot-Marie-Tooth disease, an inherited neurodegenerative disease. We are studying the effects that these mutations have on neurofilament assembly and transport to try and understand how these mutations lead to neurodegeneration. We are also studying the microtubule associated protein tau. One of the hallmarks of Alzheimer's Disease is the presence of paired helical filaments, which are composed of tau. Recent studies have identified mutations in tau in a hereditary neurodegenerative disease, frontotemporal Dementia with Parkinsonism. By using transgenic models, we hope to determine how these mutations might lead to neurodegeneration
In recent studies, we have also focused on a family of cytoskeletal linker proteins called plakins. These proteins connect cytoskeletal elements to each other and to junctional complexes. They consist of combinations of interacting domains, which include domains that bind to microfilaments, microtubules, intermediate filaments, cell adhesion molecules, as well as members of the catenin family. Mutations in these proteins lead to a variety of cellular defects, including skin blistering, muscular dystrophy and axonal outgrowth defects. Two proteins, microtubule actin crosslinking factor (MACF) and Bullous Pemphiogid Antigen 1 (BPAG1) are expressed in the muscle and the nervous system. The neuronal isosforms of these proteins are involved in axon outgrowth. We are identifying their interactions partners and and we are studying the functions of these proteins in vivo.
Selected publicationsLeung C.L., Zheng M., Prater S,M and Liem R.K.H. The BPAG1 locus: alternative splicing produces multiple isoforms with distinct cytoskeletal linker domains, including predominant isoforms in neurons and muscles. J. Cell Biol. In press.
Sun, D., Leung, C.L. and Liem, R.K.H. 2001. Characterization of the microtubule binding domain of Microtubule Actin Crosslinking Factor (MACF): identification of a novel group of microtubule associated proteins. J. Cell. Sci.114:161-172.
Wang, L., Ho, C.-L., Sun, D., Liem, R.K.H. and Brown, 2000. A. Rapid movement of axonal neurofilaments interrupted by prolonged pauses. Nature Cell Biol. 2:137-141.
Leung, C.L., Sun, D., Zheng, M., Knowles, D.R. and Liem, R.K.H. 1999. Microtubule Actin Cross-Linking Factor (MACF): A hybrid of dystonin and dystrophin that can interact with the actin and microtubule cytoskeletons. J. Cell Biol. 147:1275-1285.
Ching, G.Y., Chien, C.-L., Flores, R. G and Liem, R.K.H. 1999. Overexpression of a-internexin causes abnormal neurofilamentous accumulations and motor coordination deficits in transgenic mice. J. Neurosci.19:2974-2986.