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. pmc Clinical neurogenetics: amyotrophic lateral sclerosis
    Matthew B Harms
    Neuromuscular Division, Department of Neurology, Hope Center for Neurological Disorders, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA Electronic address
    Neurol Clin 31:929-50. 2013
  2. pmc Targeting RNA foci in iPSC-derived motor neurons from ALS patients with a C9ORF72 repeat expansion
    Dhruv Sareen
    Regenerative Medicine Institute, Cedars Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA
    Sci Transl Med 5:208ra149. 2013
  3. pmc Prion-like nuclear aggregation of TDP-43 during heat shock is regulated by HSP40/70 chaperones
    Maria Udan-Johns
    Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA
    Hum Mol Genet 23:157-70. 2014
  4. pmc Dynein mutations associated with hereditary motor neuropathies impair mitochondrial morphology and function with age
    Judith Eschbach
    Inserm U1118, Strasbourg F 67085, France
    Neurobiol Dis 58:220-30. 2013
  5. pmc TDP-43: the relationship between protein aggregation and neurodegeneration in amyotrophic lateral sclerosis and frontotemporal lobar degeneration
    Robert H Baloh
    Neuromuscular Division, Department of Neurology, Hope Center for Neurological Disorders, Washington University, Saint Louis, MO 63110, USA
    FEBS J 278:3539-49. 2011
  6. pmc Sir-two-homolog 2 (Sirt2) modulates peripheral myelination through polarity protein Par-3/atypical protein kinase C (aPKC) signaling
    Bogdan Beirowski
    Department of Genetics, Washington University School of Medicine, St Louis, MO 63110, USA
    Proc Natl Acad Sci U S A 108:E952-61. 2011
  7. pmc Exome sequencing reveals DNAJB6 mutations in dominantly-inherited myopathy
    Matthew B Harms
    Department of Neurology, Hope Center for Neurological Diseases, Washington University School of Medicine, St Louis, MO 63110, USA
    Ann Neurol 71:407-16. 2012
  8. pmc Mitofusin2 mutations disrupt axonal mitochondrial positioning and promote axon degeneration
    Albert L Misko
    Department of Neurology and Genetics, Washington University School of Medicine, St Louis, MO 63110, USA
    J Neurosci 32:4145-55. 2012
  9. pmc Mutations in the tail domain of DYNC1H1 cause dominant spinal muscular atrophy
    M B Harms
    Department of Neurology, Hope Center for Neurological Disease, Washington University School of Medicine, St Louis, MO, USA
    Neurology 78:1714-20. 2012
  10. pmc Schwann cell mitochondrial metabolism supports long-term axonal survival and peripheral nerve function
    Andreu Viader
    Department of Genetics, Washington University School of Medicine, St Louis, Missouri 63110, USA
    J Neurosci 31:10128-40. 2011

Scientific Experts

  • Robert H Baloh
  • Matthew B Harms
  • Jeffrey Milbrandt
  • Iga Wegorzewska
  • Shaughn Bell
  • M B Harms
  • Conrad C Weihl
  • Andreu Viader
  • Maria Udan
  • Yo Sasaki
  • Maria Udan-Johns
  • Dhruv Sareen
  • Judith Eschbach
  • Albert L Misko
  • Jieya Shao
  • Marc I Diamond
  • M Al-Lozi
  • Robert E Schmidt
  • A Pestronk
  • P Allred
  • Bogdan Beirowski
  • Albert Misko
  • Rodrigo A Fuentealba
  • Jufang Chang
  • Heather L True
  • Rocio Bengoechea
  • Leonard Petrucelli
  • Pratap Meera
  • C Frank Bennett
  • John Ravits
  • Michael E Shy
  • Jamal Bouitbir
  • Jean Philippe Loeffler
  • Albert C Ludolph
  • Anna Isabel Schlagowski
  • Sharon Carmona
  • Nadia Messadeq
  • Frederique Rene
  • Frank Rigo
  • Yves Larmet
  • Jacqueline G O'Rourke
  • Clive N Svendsen
  • Anais Sahabian
  • Patrick Weydt
  • Sharday Grant
  • Loren Ornelas
  • Michael Baughn
  • A K M G Muhammad
  • Anissa Fergani
  • Megan Simpkinson
  • Thomas S Otis
  • Joffrey Zoll
  • Bernard Geny
  • J√©rome Sinniger
  • Luc Dupuis
  • Tania Gendron
  • Vincent Marion
  • M Scoto
  • R Brian Sommerville
  • S Masi
  • E P Tuck
  • A Jani-Acsadi
  • L J Miller
  • Peggy Allred
  • Duanduan Ma
  • M M Reilly
  • Paul Cooper
  • Glenn Lopate
  • D Ma
  • K M Ori-McKenney
  • Alan Pestronk
  • F Muntoni
  • M E Shy
  • S Bell
  • R B Vallee
  • Elizabeth Tuck
  • Brian J North
  • Judy P Golden
  • Johan Auwerx
  • Hiroyasu Yamamoto
  • Judith P Golden
  • Shaday Michan
  • Jason Gustin
  • David A Sinclair
  • Daniel A Hunter
  • Sean M Armour
  • J A Fernandes Filho
  • R Gardner
  • J Florence
  • Sirui Jiang

Detail Information

Publications20

  1. pmc Clinical neurogenetics: amyotrophic lateral sclerosis
    Matthew B Harms
    Neuromuscular Division, Department of Neurology, Hope Center for Neurological Disorders, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA Electronic address
    Neurol Clin 31:929-50. 2013
    ....
  2. pmc Targeting RNA foci in iPSC-derived motor neurons from ALS patients with a C9ORF72 repeat expansion
    Dhruv Sareen
    Regenerative Medicine Institute, Cedars Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA
    Sci Transl Med 5:208ra149. 2013
    ..These data show that patient-derived motor neurons can be used to delineate pathogenic events in ALS. ..
  3. pmc Prion-like nuclear aggregation of TDP-43 during heat shock is regulated by HSP40/70 chaperones
    Maria Udan-Johns
    Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA
    Hum Mol Genet 23:157-70. 2014
    ....
  4. pmc Dynein mutations associated with hereditary motor neuropathies impair mitochondrial morphology and function with age
    Judith Eschbach
    Inserm U1118, Strasbourg F 67085, France
    Neurobiol Dis 58:220-30. 2013
    ..Our results show that dynein function is required for the maintenance of mitochondrial morphology and function with aging and suggest that mitochondrial dysfunction contributes to dynein-dependent neurological diseases, such as SMA-LED...
  5. pmc TDP-43: the relationship between protein aggregation and neurodegeneration in amyotrophic lateral sclerosis and frontotemporal lobar degeneration
    Robert H Baloh
    Neuromuscular Division, Department of Neurology, Hope Center for Neurological Disorders, Washington University, Saint Louis, MO 63110, USA
    FEBS J 278:3539-49. 2011
    ..This review discusses observations from human pathology, cell culture and animal model systems, to highlight our somewhat murky understanding of the relationship between TDP-43 aggregation and neurodegeneration...
  6. pmc Sir-two-homolog 2 (Sirt2) modulates peripheral myelination through polarity protein Par-3/atypical protein kinase C (aPKC) signaling
    Bogdan Beirowski
    Department of Genetics, Washington University School of Medicine, St Louis, MO 63110, USA
    Proc Natl Acad Sci U S A 108:E952-61. 2011
    ..These results demonstrate that Sirt2 controls an essential polarity pathway in SCs during myelin assembly and provide insights into the association between intracellular metabolism and SC plasticity...
  7. pmc Exome sequencing reveals DNAJB6 mutations in dominantly-inherited myopathy
    Matthew B Harms
    Department of Neurology, Hope Center for Neurological Diseases, Washington University School of Medicine, St Louis, MO 63110, USA
    Ann Neurol 71:407-16. 2012
    ..To identify the causative gene in an autosomal dominant limb-girdle muscular dystrophy (LGMD) with skeletal muscle vacuoles...
  8. pmc Mitofusin2 mutations disrupt axonal mitochondrial positioning and promote axon degeneration
    Albert L Misko
    Department of Neurology and Genetics, Washington University School of Medicine, St Louis, MO 63110, USA
    J Neurosci 32:4145-55. 2012
    ....
  9. pmc Mutations in the tail domain of DYNC1H1 cause dominant spinal muscular atrophy
    M B Harms
    Department of Neurology, Hope Center for Neurological Disease, Washington University School of Medicine, St Louis, MO, USA
    Neurology 78:1714-20. 2012
    ..To identify the gene responsible for 14q32-linked dominant spinal muscular atrophy with lower extremity predominance (SMA-LED, OMIM 158600)...
  10. pmc Schwann cell mitochondrial metabolism supports long-term axonal survival and peripheral nerve function
    Andreu Viader
    Department of Genetics, Washington University School of Medicine, St Louis, Missouri 63110, USA
    J Neurosci 31:10128-40. 2011
    ..Mitochondrial function in SCs is therefore essential for maintenance of axonal survival and normal peripheral nerve function, suggesting that SC mitochondrial dysfunction contributes to human peripheral neuropathies...
  11. pmc Implications of the prion-related Q/N domains in TDP-43 and FUS
    Maria Udan
    Department of Neurology, Neuromuscular Division, Washington University, Saint Louis, MO, USA
    Prion 5:1-5. 2011
    ..This review discusses the potential relevance of the prion-related domains in TDP-43 and FUS in normal physiology, pathologic aggregation, and disease progression in ALS and FTLD...
  12. pmc TDP-43-based animal models of neurodegeneration: new insights into ALS pathology and pathophysiology
    Iga Wegorzewska
    Neuromuscular Division, Department of Neurology, Washington University, Saint Louis, MO 63110, USA
    Neurodegener Dis 8:262-74. 2011
    ..This review will compare the features of numerous recently developed animal models of TDP-43-related neurodegeneration, and discuss how they contribute to our understanding of the pathogenesis of human ALS and FTLD...
  13. pmc Dominant spinal muscular atrophy with lower extremity predominance: linkage to 14q32
    M B Harms
    Department of Neurology, Washington University School of Medicine, St Louis, MO 63110, USA
    Neurology 75:539-46. 2010
    ..We aimed to clinically, pathologically, and genetically characterize a large North American family with an autosomal dominant proximal SMA...
  14. pmc Interaction with polyglutamine aggregates reveals a Q/N-rich domain in TDP-43
    Rodrigo A Fuentealba
    Department of Neurology, Washington University School of Medicine, St Louis, Missouri 63110, USA
    J Biol Chem 285:26304-14. 2010
    ....
  15. pmc Mitofusin 2 is necessary for transport of axonal mitochondria and interacts with the Miro/Milton complex
    Albert Misko
    Department of Neurology and Hope Center for Neurological Diseases, Washington University School of Medicine, St Louis, Missouri 63110, USA
    J Neurosci 30:4232-40. 2010
    ....
  16. 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
    ....
  17. 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...
  18. 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...
  19. 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
    ....
  20. 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
    ....