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Ronald K. Liem, PhD

Academic Appointments

  • Professor of Pathology & Cell Biology
Ronald K. Liem, PhD
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.

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.

Departmental Appointments

  • Department of Pathology & Cell Biology

Lab Locations

  • 630 West 168th Street
    P&S 15-421
    New York, NY 10032
    Phone:
    (212) 305-4078
    Fax:
    (212) 305-5498
    Email:
    rkl2@cumc.columbia.edu

Research Interests

  • Neural Degeneration and Repair
  • Cellular/Molecular/Developmental Neuroscience

NIH Grants

  • ROLE OF PHOSPHOINOSITIDES IN NEURONAL MEMBRANE TRAFFIC AND NEURODEGENERATION (Federal Gov)

    Jul 1 2006 - Dec 31 2017

    TRAINING IN CELLULAR, MOLECULAR AND BIOMEDICAL STUDIES (Federal Gov)

    Jul 1 2012 - Jun 30 2017

    DECIPHERING THE METABOLISM OF LBPA AND ITS FUNCTION IN THE ENDOLYSOSOMAL SYSTEM (Federal Gov)

    Jul 1 2014 - Jun 30 2016

    CHARACTERIZATION OF A NEW MOUSE MODEL FOR CMT2E (Private)

    Feb 1 2013 - Jan 31 2016

    GENERATION OF CELL LINES FOR CMT2E DRUG SCREENING (Private)

    Nov 1 2012 - Oct 31 2014

    INTERNATIONAL STUDENT RESEARCH FELLOWSHIP (Private)

    Sep 1 2011 - Aug 31 2014

    TRAINING PROGRAM IN MOLECULAR BASIS OF HEALTH AND DISEASE (Private)

    Apr 1 2010 - Mar 31 2014

    IDENTIFICATION OF COMPOUNDS TO TREAT CHARCOT-MARIE-TOOTH TYP E 2E NEUROPATHY (Federal Gov)

    Jul 1 2009 - Aug 31 2012

    TRANSGENIC MOUSE MODELS FOR ALZHEIMER DISEASE (Private)

    Jul 1 2007 - Aug 31 2009

Publications

  • 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