Mechanism of Peripheral Neuropathy from Mitofusin 2 Mutations

Summary

Principal Investigator: ROBERT HARRIS BALOH
Affiliation: Washington University School of Medicine
Country: USA
Abstract: The candidate is an MD/PhD trained clinical neurologist with the career goal to investigate the mechanisms of neurodegeneration in peripheral neuropathies, using axonal Charcot-Marie-Tooth (CMT) as a prototypical disease. The career development plan will be jointly mentored by Dr. Alan Pestronk, a clinical expert in neuromuscular disorders, and Dr. Jeffrey Milbrandt whose lab focuses on molecular mechanisms of axonal degeneration and peripheral neuropathy - a unique merger allowing the candidate to become a successful independent investigator in this field. CMT neuropathies are among the most common inherited conditions of the nervous system, and currently are without treatment. They provide an opportunity for the clinician-scientist to understand the mechanisms of axonal degeneration in the peripheral nervous system, which likely will have broader implications for neurodegenerative disorders. Mitofusin 2 (MFN2) mutations are the most frequently identified cause of the axonal form of CMT (CMT2A), but the mechanism by which they lead to axonal degeneration is unknown. MFN2 is a mitochondrial membrane protein that is a critical component of the mitochondrial fusion apparatus, required for proper mitochondrial function. Our primary hypothesis is that MFN2 mutations lead to altered axonal mitochondrial transport and/or mitochondrial fusion, resulting in mitochondrial dysfunction, energy depletion and degeneration of distal peripheral axons. We will test this hypothesis by 1) introducing disease mutant forms of MFN2 seen in CMT2A patients into cultured sensory neurons, and examining their effect on axonal mitochondrial transport, mitochondrial fusion and oxidative function; and 2) generating a transgenic mouse model of CMT2A to study the detailed pathogenesis of the disease, corroborate our in vitro findings in an in vivo disease model, and to potentially provide a means of testing therapeutic agents for peripheral neuropathy and axonal degeneration in future studies. Relevance: Peripheral neuropathies, particularly those caused by metabolic disorders such as diabetes are a major cause of morbidity in the United States, yet the mechanisms of peripheral neuropathy remain poorly understood and there are no effective treatments. This proposal outlines research to understand the mechanism of an inherited form of peripheral neuropathy, in the hopes that this will provide insight, and eventually lead to effective treatments, for more commonly encountered types of neuropathy.
Funding Period: 2007-07-01 - 2012-06-30
more information: NIH RePORT

Top Publications

  1. ncbi Mitochondrial dynamics and peripheral neuropathy
    Robert H Baloh
    Hope Center for Neurological Disorders, Washington University, Saint Louis, Missouri 63110, USA
    Neuroscientist 14:12-8. 2008
  2. pmc Congenital hypomyelinating neuropathy with lethal conduction failure in mice carrying the Egr2 I268N mutation
    Robert H Baloh
    Department of Neurology, and Hope Center for Neurological Diseases, Washington University School of Medicine, St Louis, Missouri 63110, USA
    J Neurosci 29:2312-21. 2009
  3. pmc Transgenic mice expressing the Nmnat1 protein manifest robust delay in axonal degeneration in vivo
    Yo Sasaki
    Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA
    J Neurosci 29:6526-34. 2009
  4. pmc The NIMA-family kinase Nek3 regulates microtubule acetylation in neurons
    Jufang Chang
    Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA
    J Cell Sci 122:2274-82. 2009
  5. pmc TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration
    Iga Wegorzewska
    Department of Neurology and Hope Center for Neurological Diseases, Washington University School of Medicine, St Louis, MO 63110, USA
    Proc Natl Acad Sci U S A 106:18809-14. 2009

Scientific Experts

  • Robert H Baloh
  • Yo Sasaki
  • Jeffrey Milbrandt
  • Iga Wegorzewska
  • Jufang Chang
  • Nigel J Cairns
  • Shaughn Bell
  • Bhupinder P S Vohra
  • Timothy M Miller

Detail Information

Publications5

  1. ncbi Mitochondrial dynamics and peripheral neuropathy
    Robert H Baloh
    Hope Center for Neurological Disorders, Washington University, Saint Louis, Missouri 63110, USA
    Neuroscientist 14:12-8. 2008
    ....
  2. pmc Congenital hypomyelinating neuropathy with lethal conduction failure in mice carrying the Egr2 I268N mutation
    Robert H Baloh
    Department of Neurology, and Hope Center for Neurological Diseases, Washington University School of Medicine, St Louis, Missouri 63110, USA
    J Neurosci 29:2312-21. 2009
    ....
  3. pmc Transgenic mice expressing the Nmnat1 protein manifest robust delay in axonal degeneration in vivo
    Yo Sasaki
    Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA
    J Neurosci 29:6526-34. 2009
    ..These results highlight the importance of understanding the mechanism of Nmnat-mediated axonal protection for the development of new treatment strategies for neurological disorders...
  4. pmc The NIMA-family kinase Nek3 regulates microtubule acetylation in neurons
    Jufang Chang
    Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA
    J Cell Sci 122:2274-82. 2009
    ..The deacetylation of microtubules in neurons by unphosphorylated Nek3 raises the possibility that it could have a role in disorders where axonal degeneration is an important component...
  5. pmc TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration
    Iga Wegorzewska
    Department of Neurology and Hope Center for Neurological Diseases, Washington University School of Medicine, St Louis, MO 63110, USA
    Proc Natl Acad Sci U S A 106:18809-14. 2009
    ....