Departments And Divisions
- Department of Pathology & Cell Biology
- Professor of Pathology & Cell Biology
The focus of research in my laboratory is the study of the neuronal cytoskeleton and its relationship to neurodegenerative disease, in particular the neuronal intermediate filament proteins. Heurofilaments in both the central and peripheral nervous system are composed primarily of triplet proteins: NFL, NFM, and NFH (for light, middle, and high molecular with neurofilament protein) that are encoded by the NEFL, NEFM and NEFH genes respectively. Abnormal neurofilamentous accumulations have long been described as being present in neuronal processes and cell bodies in various neurodegenerative diseases. A clear link between mutations in the gene for the neurofilament light protein (NEFL) and neurodegenerative diseases has been established in Charcot-Marie-Tooth disease, where as many as sixteen dominant mutations have been identified. These dominant mutations in the NFL protein result in the formation of neurofilamentous accumulations that cause abnormalities in mitochondrial and slow axonal transport, as well as neuritic degeneration. In cell transfection studies, we have shown a correlation between the presence of pathogenic mutations in NEFL and abnormal assembly of the filaments in both neuronal and non-neuronal cells. We have generated a knock-in mouse model with one of the mutations, N98S. This N98S/+ Neflmouse recapitulates most of the features of patients with this mutation. The animals have a tremor and showed decrease in balance. Immunohistochemical analyses showed multiple inclusions in the cell bodies and axons of spinal cord neurons and dorsal root ganglia , disorganized processes in the cerebellum, and abnormal processes in the cerebral cortex and pons. Abnormal processes were observed as early as post-natal day 7. Electron microscopic analysis of sciatic nerves showed a reduction in the number of neurofilaments, an increase in the number of microtubules and a decrease in the axonal diameters. We have conducted ultrastructural analyses of cultured dorsal root ganglia (DRG) from NeflN98S/+ mice and showed that inclusions found in DRG soma and neurites can occur in embryonic stages. These studies also revealed that the inclusions are disordered neurofilaments packed in high density, segregated from other organelles
This N98S/+ Nefl mouse provides an excellent model to study the pathogenesis of the neurodegeneration observed in human Charcot-Marie-Tooth type 2, and should prove useful for testing potential therapies. Further studies using motor neurons derived from the ES cells that were used to generate the mice, as well as cultured dorsal root ganglia from these mice are currently underway.
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- Neural Degeneration and Repair
- Cellular/Molecular/Developmental Neuroscience
- Zhao, J., K. Brown, and R.K.H. Liem. 2017. Abnormal neurofilament inclusions and segregations in dorsal root ganglia of a Charcot-Marie-Tooth type 2E mouse model. PloS one. 12:e0180038.
- Omary, M.B., and R.K. Liem. 2016. Editors. Intermediate Filament Proteins Methods Enzymol. vol. 568
- Zhao, J., and R.K. Liem. 2016. Alpha-Internexin and Peripherin: Expression, Assembly, Functions, and Roles in Disease. Methods Enzymol. 568:477-507
- Liem, R.K. 2016. Cytoskeletal Integrators: The Spectrin Superfamily. Cold Spring Harb Perspect Biol. 8.
- Adebola, A.A., T. Di Castri, C.Z. He, L.A. Salvatierra, J. Zhao, K. Brown, C.S. Lin, H.J. Worman, and R.K. Liem. 2015. Neurofilament light polypeptide gene N98S mutation in mice leads to neurofilament network abnormalities and a Charcot-Marie-Tooth Type 2E phenotype. Human molecular genetics. 24:2163-2174.
- Saporta, M.A., V. Dang, D. Volfson, B. Zou, X.S. Xie, A. Adebola, R.K. Liem, M. Shy, and J.T. Dimos. 2015. Axonal Charcot-Marie-Tooth disease patient-derived motor neurons demonstrate disease-specific phenotypes including abnormal electrophysiological properties. Experimental neurology. 263:190-199.
- Goryunov, D., C.Z. He, C.S. Lin, C.L. Leung, and R.K. Liem. 2010. Nervous-tissue-specific elimination of microtubule-actin crosslinking factor 1a results in multiple developmental defects in the mouse brain. Molecular and cellular neurosciences. 44:1-14.
- Perez-Olle R, Jones ST, Liem R.K.H. 2004. Phenotypic analysis of neurofilament light gene mutations linked toCharcot-Marie-Tooth disease in cell culture models. Human Molecular Genetics 13:2207-20
- 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).
For a complete list of publications, please visit PubMed.gov