Departments And Divisions
- Department of Pathology & Cell Biology
- Professor of Pathology & Cell Biology
The neuronal cytoskeleton consists of three types of interlinked cytoskeletal elements, the microtubules (MTs), the microfilaments and the neuronal intermediate filaments (IFs). In amyotropic lateral sclerosis, neurofilamentous accumulations are observed in the cell bodies and proximal axons of motor neurons. We hypothesize that defects in microtubule dependent transport of neurofilaments lead to the abnormal accumulations of neurofilaments that typify a number of neurodegenerative diseases. Recently, dominant mutations in the neurofilament light chain (NFL) gene have been described as the primary cause of an axonal form of Charcot-Marie Tooth (CMT2) disease. We have made the mutations in NFL cDNAs and found that these mutant NFL proteins have abnormal assembly properties and transport properties. We are characterizing the downstream effects of the NF mutations in neuronal cells and in transgenic animals.
The mutant mouse dystonia musculorum (dt) suffers from a severe hereditary sensory neuropathy. Focal axonal swellings filled with neurofilaments, mitochondria and membrane bound dense bodies are hallmarks of the pathology of these mice. The gene that is mutated in dt mice is known as bullous pemphigoid antigen 1 (BPAG1). BPAG1 belongs to the plakin family that is involved in the interaction of the cytoskeleton with epithelial junctions. We have shown that different isoforms of BPAG1 are expressed in epithelia, muscle and neurons. The neuronal isoform of BPAG1 can associate with all three cytoskeletal systems, as well as cell adhesion and junctional proteins. We are characterizing the role of BPAG1 in the nervous system to understand the specific defects that lead to the sensory neuropathy in these mice.
In a related project, we are also studying a protein called MACF (Microtubule actin crosslinking factor). MACF and BPAG1 are both members of the plakin family and have similar domain structures, but studies from knock-out mice indicate that they have distinct functions. MACF is ubiquitously expressed in the mouse embryo with high expression in the nervous system. Mutations in Shortstop, the Drosophila homologue of MACF cause defects in muscle-tendon cell differentiation, local development of neuronal processes and axonal outgrowth. The properties of shortstop make MACF a potential key player in axonal outgrowth and we are studying the function and interaction partners of MACF in more detail.
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- Neural Degeneration and Repair
- Cellular/Molecular/Developmental Neuroscience
- Lin C.M, Chen H.J, Leung C.L, Parry D.A, andLiem R.KH. Microtubule actin crosslinking factor 1b: a novel plakinthat localizes to the Golgi complex. J Cell Sci. 118:3727-38 (2005)
- Perez-Olle R, Jones ST, Liem R.K.H. Phenotypicanalysis of neurofilament light gene mutations linked toCharcot-Marie-Tooth disease in cell culture models. Hum Mol Genet. 200413:2207-20 (2004)
- Jefferson,J. and Liem, R.K.H. Plakins, Goliaths at the interface of celljunctions and the cytoskeleton. Nature Revs. Cell Mol. Biol. 5:542-553.(2004).
- Liem,R.K.H. and Leung, C.L. Neuronal intermediate filamentoverexpression andneurodegeneration in transgenic mice. Exp. Neur.184:3-8 (2003).
- Leung,C.L., Green, K.J. and Liem, R.K.H.: Plakins: a family ofversatilecytolinker proteins: Trends in Cell Biol. 12:37-45 (2002).
- Perez-Olle,R., Leung, C.L. and Liem, R.K.H.: Effects of Charcot-Marie-Tooth linkedmutations of the neurofilament light subunit (NFL) on intermediatefilament formation. J. Cell Sci. 115:4937-46 (2002).
- Leung C.L., Zheng M., Prater S,M and LiemR.K.H. The BPAG1 locus: alternative splicing produces multiple isoformswith distinct cytoskeletal linker domains, including predominantisoforms in neurons and muscles. J. Cell Biol. 154: 691-697 (2001).
- Wang, L.,Ho, C.-L., Sun, D., Liem, R.K.H. and Brown, A. Rapid movementof axonalneurofilaments interrupted by prolonged pauses. Nature CellBiol.2:137-41 (2000).
For a complete list of publications, please visit PubMed.gov