Lawrence Wrabetz MD
Lawrence Wrabetz
MD
Director, Hunter James Kelly Research Institute; Professor of Neurology and Biochemistry
Jacobs School of Medicine & Biomedical Sciences
Specialty/Research Focus
Developmental Neurology; Neurology
Professional Summary:
My laboratory has a longstanding interest in myelin and its diseases. Myelin surrounds large axons and permits rapid conduction of signals. It is formed by oligodendrocytes in the central nervous system, and Schwann cells in the peripheral nervous system. During development, these cells migrate with the axons that they will myelinate, and depend on those same axons for appropriate signals to survive and differentiate. Myelin-forming glia coordinately express a unique set of genes encoding myelin structural proteins, and enzymes that synthesize myelin lipids-this coordination is in large part transcriptionally-mediated. Given the unique three dimensional transformation of the cell required for myelination, many of the involved proteins include adhesion among their functions. Therefore, our projects include studies of transcriptional regulation, axonal signals to myelinating glia, the role of adhesion in myelination and the characterization of animal models of human demyelinating diseases.
Education and Training:
- Fellowship, Neuroscience, University of Pennsylvania School of Medicine (1991)
- Residency, Neurology, University of Pennsylvania School of Medicine (1988)
- MD, Medicine and Surgery, University of Chicago Pritzker School of Medicine, (Honors) (1984)
- BS, Chemistry, Marquette University, Summa Cum Laude (1980)
Employment:
- Professor, Departments of Neurology and Biochemistry, State University of New York at Buffalo, School of Medicine and Biomedical Sciences (2011-present)
- Director, HJKRI-Hunter James Kelly Research Institute, State University of New York at Buffalo, School of Medicine and Biomedical Sciences (2011-present)
- Adjunct Member, Cancer Center Genetics Program, Roswell Park Cancer Institute (2011-present)
- Head of Unit: Biology of Myelin, San Raffaele Scientific Institute, DIBIT, Italy (1995–2011)
- Researcher, Dept. Genetics and Cell Biology, San Raffaele Scientific Institute, DIBIT, Italy (1993–2011)
- Lecturer, Department of Neurology, University of Pennsylvania, School of Medicine (1991–1993)
Research Expertise:
- Developmental neurology
- Leukodystrophy
Research Centers:
- Center of Excellence in Bioinformatics and Life Sciences
UB 2020 Strategic Strengths:
- Molecular Recognition in Biological Systems and Bioinformatics
Grants and Sponsored Research:
- December 2007–December 2020
Grants and Sponsored Research(selected)
Role: Principal Investigator - April 2010–June 2015
Empire State Development Corporation - Krabbe Disease Research Capital Equipment
NY
Role: Principal Investigator
$6,000,000 - September 2010–December 2013
Telethon Program Project: Modulating Neuregulin-1 signals to treat hereditary demyelinating neuropathies
Role: Principal Investigator
$406,100 - October 2012–September 2013
Empire State Development Corporation, The Research Foundation - Krabbe Disease Research Working Capital
NY
Role: Principal Investigator
$980,000 - February 2006–January 2012
NIH: R01 NS055256 Pathogenesis of Myelin Protein Zero Neuropathies in Transgenic Mice
Role: Principal Investigator
$1,215,000 - February 2009–January 2011
Fondazione Mariani: Side by Side analysis of children and mice with Myelin Protein Zero Neuropathies to promote treatment strategies
Role: Principal Investigator
$186,078 - September 2007–August 2010
Telethon GGP07100: P0 glycoprotein trafficking and quality control in Charcot Marie Tooth 1B Neuropathy
Role: Principal Investigator
$487,654
Journal Articles:
- Welser-Alves JV, Boroujerdi A, Tigges U, Wrabetz L, Feltri ML, Milner R. Endothelial ß4 Integrin Is Predominantly Expressed in Arterioles, Where It Promotes Vascular Remodeling in the Hypoxic Brain.. Arterioscler Thromb Vasc Biol. 2013; 33(5).
- Sumihisa O, Henry K, Mantuano E, Yamauchi K, De Corato A, Feltri ML, Wrabetz L, Gaultier A, Ellisman M, Takahashi K, Gonias SL, & Campana WM. LRP1 expression in Schwann cells is required for prevention of chronic neuropathic pain. J Neurosci. 2013.
- D‘Antonio M, Musner N, Scapin C, Ungaro D, Del Carro U, Ron D, Feltri ML, Wrabetz L. Resetting translational homeostasis via Inactivation of Gadd34 Restores Myelination in CMT1B Mice. J Exp Med. 2013.
- Patzk� A, Bai Y, Saporta MA, Katona I, Wu X, Vizzuso D, Feltri ML, Wang S, Dillon LM, Kamholz J, Kirschner D, Sarkar FH, Wrabetz L, Shy ME. Curcumin derivatives promote Schwann cell differentiation and improve neuropathy in R98C CMT1B mice.. Brain. 2012; 135(Pt 12).
- Saporta MAC, Shy BR, Patzko A, Bai Y, Pennuto M, Ferri C, Kirschner D, Avila R, Southwood CM, Gow A, Feltri ML, Wrabetz L*, Shy ME*.. MpzR98C arrests Schwann cell development in a mouse model of early-onset Charcot-Marie-Tooth 1B. Brain. 2012; 135.
- La Marca R, Cerri F, Horiuchi K, Bachi A, Feltri ML, Wrabetz L, Blobel CP, Quattrini A, Salzer JL, Taveggia C. TACE (ADAM17) inhibits Schwann cell myelination.. Nat Neurosci. 2011; 14(7).
- Fratta P, Saveri P, Zambroni D, Ferri C, Tinelli E, Messing A, D’Antonio M, Feltri ML, Wrabetz L. P0S63del impedes the arrival of wildtype P0 glycoprotein to myelin in CMT1B mice. Hum Mol Genet. 2011; 20.
- Vaccari I, Dina G, Tronchere H, Kaufman E, Cerri F, Wrabetz L, Payrastre B. Quattrini A, Weisman L, Meisler M, Bolino A. Genetic interaction between MTMR2 and FIG4 phospholipid phosphatases involved in Charcot-Marie-Tooth neuropathies. PLoS Genet. 2011; 7(10).
- Avila RL, D‘Antonio M, Bachi A, Inouye H, Feltri ML, Wrabetz L, Kirschner DA. P0 (protein zero) mutation S34C underlies instability of internodal myelin in S63C mice.. J Biol Chem. 2010; 285(53).
- Yun B, Anderegg A, Menichella D, Wrabetz L, Feltri ML, Awatramani R. MicroRNA-deficient Schwann cells display congenital hypomyelination.. J Neurosci. 2010; 30(22).
- Woodhoo A, Alonso MB, Droggiti A, Turmaine M, D‘Antonio M, Parkinson DB, Wilton DK, Al-Shawi R, Simons P, Shen J, Guillemot F, Radtke F, Meijer D, Feltri ML, Wrabetz L, Mirsky R, Jessen KR. Notch controls embryonic Schwann cell differentiation, postnatal myelination and adult plasticity.. Nat Neurosci. 2009; 12(7).
- Verheijen MHG, Camargo N, Verdier V, Nadra K, de Preux A-S, Medard J-J, Luoma A, Crowther M, Inouye H, Shimano H, Chen S, Brouwers JF, Helms JB, Feltri ML, Wrabetz L, Kirschner D, Chrast R, Smit AB. SREBP cleavage activation protein (SCAP) is required for timely synthesis of a Schwann cell myelin membrane. PNAS. 2009; 106(50).
- Gow A, and Wrabetz L. CHOP and the endoplasmic reticulum stress response in myelinating glia. Curr Opin Neurobiol. 2009; 9(5).
- Doddrell RD, Dun XP, Shivane A, Feltri ML, Wrabetz L, Wegner M, Sock E, Hanemann CO, Parkinson DB. Loss of SOX10 function contributes to the phenotype of human Merlin-null schwannoma cells.. Brain. 2013; 136(Pt 2).
- Berti C, Bartesaghi L, Ghidinelli M, Zambroni D, Figlia G, Chen ZL, Quattrini A, Wrabetz L, Feltri ML. Non-redundant function of dystroglycan and ß1 integrins in radial sorting of axons.. Development. 2011; 138(18).
- Jin F, Dong B, Georgiou J, Jiang Q, Zhang J, Bharioke A, Qiu F, Lommel S, Feltri ML, Wrabetz L, Roder JC, Eyer J, Chen X, Peterson AC, Siminovitch KA. N-WASp is required for Schwann cell cytoskeletal dynamics, normal myelin gene expression and peripheral nerve myelination.. Development. 2011; 138(7).
- Taveggia C, Feltri ML, Wrabetz L. Signals to promote formation and repair of myelin. Nat Rev Neurol. 2010; 6(5).
- Nodari A, Previtali SC, Dati G, Occhi S, Court FA, Colombelli C, Zambroni D, Dina G, Del Carro U, Campbell KP, Quattrini A, Wrabetz L, Feltri ML, Feltri M. Alpha6beta4 integrin and dystroglycan cooperate to stabilize the myelin sheath.. J Neurosci. 2008; 28(26).
- Mager GM, Ward RM, Srinivasan R, Jang SW, Wrabetz L, Svaren J. Active gene repression by the EGR2/NAB complex during peripheral nerve myelination. J Biol Chem. 2008; 83(26).
- Parkinson DB, Bhaskaran A, Arthur-Farraj P, Noon L, Woodhoo A, Lloyd A, Ham J, Feltri ML, Wrabetz L, Behrens A, Mirsky R, Jessen KR. Negative regulation of the Schwann cell myelin phenotype: the role of c-Jun. J. Cell Biol. 2008; 181.
- Scherer SS, Wrabetz L. Molecular Mechanisms of Inherited Demyelinating Neuropathies. Glia. 2008; 56.
- Pennuto M, Tinelli E, Malaguti MC, Del Carro U, Ron D, D’Antonio M, Quattrini A, Feltri ML, Wrabetz L. Ablation of the UPR-mediator CHOP restores motor function and reduces demyelination in Charcot Marie Tooth 1B mice. Neuron. 2008; 57.
- Wrabetz L, D’Antonio M, Pennuto M, Dati G, Tinelli E, Fratta P, Previtali S, Imperiale D, Zielasek J, Toyka K, Avila R, Kirschner DA, Messing A, Feltri ML and Quattrini A. Different intracellular pathomechanisms produce diverse MPZ-neuropathies in transgenic mice. J. Neurosci. 2006; 26.
- LeBlanc SE, Jang S-W, Ward R, Wrabetz L, Svaren J. Direct regulation of Myelin Protein Zero expression by the Egr2 transactivator. J Biol Chem. 2006; 281.
- Bolino A, Bolis A, Previtali SC, Dina G, Bussini S, Dati G, Amadio S, Del Carro U, Mruk DD, Feltri ML, Cheng CY, Quattrini A, Wrabetz L. Disruption of Mtmr2 produces CMT4B1-like neuropathy with myelin outfolding and impaired spermatogenesis.. J Cell Biol. 2004; 167(4).
- Taveggia C, Pizzagalli A, Fagiani E, Messing A, Feltri ML, Wrabetz L. Characterization of a Schwann cell enhancer in the myelin basic protein gene.. J Neurochem. 2004; 91(4).
- Yin X, Kidd GJ, Pioro EP, McDonough J, Dutta R, Feltri ML, Wrabetz L, Messing A, Wyatt RM, Balice-Gordon RJ, Trapp BD. Dysmyelinated lower motor neurons retract and regenerate dysfunctional synaptic terminals.. J Neurosci. 2004; 24(15).
- Saito F, Moore SA, Henry MD, Messing A, Ross-Barta SD, Cohn RD, Williamson RA, Sluka KA, Schmelzer JA, Low PA, Wrabetz L, Feltri ML, and Campbell KP.. Unique role of dystroglycan in peripheral nerve myelination and sodium channel clustering. Neuron. 2003; 38.
- Wrabetz L, Feltri ML, Graus-Porta D, Previtali S, Nodari A, Migliavacca B, Cassetti A, Littlewood-Evans A, Reichardt L, Messing A, Quattrini A, Muller U. Conditional disruption of ß1 integrin in Schwann cells impedes interactions with axons. J Cell Biol. 2002; 156.
- Wrabetz L, Feltri ML, Quattrini A, Imperiale D, Previtali S, D’Antonio M, Martini R, Yin X, Trapp B, Xhou L, Chiu S-Y, and Messing A. P0 overexpression causes congenital hypomyelination of peripheral nerves. J Cell Biol. 2000; 148.
- Feltri ML, D‘Antonio M, Previtali S, Fasolini M, Messing A, Wrabetz L. P0-Cre transgenic mice for inactivation of adhesion molecules in Schwann cells.. Ann N Y Acad Sci. 1999; 883.
- Wrabetz L. A novel Po glycoprotein transgene activates expression of lacZ in myelin-forming Schwann cells. Eur J Neurosci. 1999; 11.
- Taveggia C, Pizzagalli A, Feltri ML, Grinspan JB, Kamholz J, Wrabetz L. MEBA derepresses the proximal myelin basic protein promoter in oligodendrocytes.. J Biol Chem. 1998; 273(42).
- Wrabetz L, Taveggia C, Feltri ML, Quattrini A, Awatramani R, Scherer SS, Messing A, Kamholz J. A minimal human MBP promoter-lacZ transgene is appropriately regulated in developing brain and after optic enucleation, but not in shiverer mutant mice.. J Neurobiol. 1998; 34(1).
- Feltri ML, Scherer SS, Nemni R, Kamholz J, Vogelbacker H, Scott MO, Canal N, Quaranta V, Wrabetz L. Beta 4 integrin expression in myelinating Schwann cells is polarized, developmentally regulated and axonally dependent.. Development. 1994; 120(5).
Books and Book Chapters:
- Wrabetz L, Feltri ML, Kleopa K, Scherer S. Inherited Neuropathies- Clinical, Genetic, and Biological Features. In Lazzarini, R (ed.), Myelin Biology and Disorders, Academic Press, San Diego, 2004, 905-951..
- Wrabetz L, Feltri ML, Suter U. Animals Models of Charcot-Marie-Tooth Disease. In Lazzarini, R (ed.), Myelin Biology and Disorders, Academic Press, San Diego, 2004, 1143-1168..
- Kirschner D, Wrabetz L, Feltri ML. P0: Gene, Protein, Function. In Lazzarini, R (ed.), Myelin Biology and Disorders, Academic Press, San Diego, 2004, 523-545..
- Scherer SS, Feltri ML, Wrabetz L. Genetic Mutations Affecting Myelination. In Kettenmann H, Ransom BR (ed.), Neuroglia, 3rd ed. Oxford University Press, Oxford, UK, 2012, 796-806..
Presentations:
- "Presentations: Oral Presentations/Symposia Chair by Invitation (selected):" (2013)
- "Pathogenesis in Hereditary Demyelinating Neuropathies: Toxic Mechanisms Target Development" Richard P. Bunge Memorial Lecture in Neuroscience, University of Miami (2013)
- "Endoplasmic Reticulum Stress and Translational Homeostasis in Myelinating Glia" Conference on Glia in Disease, University of Rochester, CTSI Symposium (2012)
- "ER Stress in Glia and Neurodegeneration" , University of Buffalo, Molecular Basis of Neurodegenerative Disorders (2012)
- "Preclinical Studies in Animals" Muscle Study Group Scientific Meeting (2012)
- "Pathogenesis in CMT Neuropathy versus Krabbe Leukodystrophy" 2nd Krabbe Translational Research Network, University of Pittsburgh (2012)
- "Toxic Mechanisms Impact Development in Hereditary Neuropathies" , Washington University School of Medicine, Department of Developmental Biology (2012)
- "Translational Homeostasis as a Therapeutic Target in CMT1B Neuropathy" 8th Great Lakes Glia Meeting (2011)
- "Translational Homeostasis as a Therapeutic Target in ER stress Diseases" ISN Satellite Meeting on Myelin Biology (2011)
- "Translational Homeostasis as a Therapeutic Target in ER Stress Diseases" Translational Homeostasis as a Therapeutic Target in ER Stress Diseases (2011)
- "Genetic Background and CMT animal models" European Neuromuscular Center, Outcome Measures in Rodent Models of CMT (2011)
- "Translational Homeostasis as a Therapeutic Target in ER Stress Diseases" MRC Centre for Neuromuscular Diseases, University College London (2010)
- "Schwann cell pathways in inherited demyelinating neuropathies" World Federation of Neurology-XII International Congress on Neuromuscular Diseases, World Federation of Neurology-XII International Congress, Pathogenic Mechanisms of Inherited Neuropathies (2010)
- "Toxic Mechanisms in Hereditary Neuropathy" ISF-Legacy Heritage Fund Inaugural Meeting On New Approaches To Neurodegenerative Diseases (2010)
- "Endoplasmic reticulum stress impedes differentiation and translational homeostasis in hereditary demyelinating neuropathy" , CSIC Institute of Neuroscience, UMH (2009)
- "Altered translational control is pathogenetic in CMT1B mice" , Myelin Satellite to International Society for Neurochemistry (2009)
- "P0S63del impedes the arrival of wildtype P0 glycoprotein to myelin in CMT1B mice" CMT Meeting (2009)
- "Cell stress signals and peripheral neuropathy" , IFTZ Medizinische Universität (2008)
- "Packing defects or cell stress modulate hereditary demyelinating neuropathy" , University of Illinois (2008)
- Gordon Conference Myelin, Glial cell death and axonal pathology (2008)
- "Intracellular pathogenesis and phenotype in CMT neuropathies" Glial Cells in Health & Disease: The VIIIth European Meeting, The Molecular Pathology of Myelination (2007)
- "Inherited Neuropathies and Schwann cells" Peripheral Nerve Society Meeting (2007)
- "MTMR2 phospholipid phosphatase, CMT4B, and membrane trafficking in Schwann cells" Second European and North American Charcot-Marie-Tooth Consortium Meeting, Cell Biology of CMT (2007)
- "Endoplasmic reticulum stress and pathogenesis of CMT1B neuropathy" , European Neurochemical Society, : Inherited Peripheral Neuropathies and Schwann cell Biology (2007)
- "Pathogenetic basis for phenotypic variation in CMT neuropathies" International Symposium on CMT neuropathies, German Congress for Muscle Pathology (2007)
- "Pathological Protein Quality Control in Hereditary Neuropathy" Director’s Seminar Series, National Institute of Neurological Disorders and Stroke, NIH (2006)
- "Pitfalls of Translational Research for Genetic Diseases—The Plus and Minus of Animal Models" Translational Research Forum, National Institute of Neurological Disorders and Stroke, NIH (2006)
- "Transgenic Mouse Models of Phenotypic Diversity in Hereditary Demyelinating Neuropathies" , University of Torino, University of Torino (2006)
- "Unfolded Protein Response: A Cause for demyelinating Charcot Marie Tooth Neuropathy" Interdepartmental Seminar Series, University of Bonn (2006)
- "ER Stress Modulates Demyelinating CMT Neuropathy in Transgenic Mice" , Albert Einstein School of Medicine, Department of Neuroscience (2006)
- "Myelin Protein Zero trafficking and quality control in Charcot-Marie-Tooth neuropathies" Myelin Gordon Conference (2006)
- "Intracellular pathogenesis of childhood-onset hereditary neuropathies" , University of Antwerp (2006)
- "Intracellular pathogenesis of childhood-onset hereditary neuropathies" Research advances in developmental neurosciences and paediatric neurology, Congress of the European Academy of Childhood Disability (2005)
- "Protein Quality Control of P0 Glycoprotein in Hereditary Neuropathies" Jordi Folch-Pi Memorial Symposium, American Society for Neurochemistry, Progress on the pathogenesis of hereditary neurodegenerative disorders (2005)
- "Gain of abnormal function and phenotypic diversity in MPZ-related neuropathies" Second Annual Symposium of the North American Charcot-Marie-Tooth Consortium, Ann Lee Beyer Plenary Lecture (2005)
- "Protein quality control in the pathogenesis of CMT1B hereditary neuropathy" Dutch Endo-Neuro-Psycho Meeting (2005)
- "Importance of defined genetic background to experimental design" , Charles River Laboratories European Short Course (2005)
- "Protein Quality Control of P0 Glycoprotein in Mouse Models of Hereditary Neuropathies" , Vienna BioCenter (IBMA, IMP & Univ Vienna) and Austrian Society of Genetics (2004)
- "Transgenic mouse models of CMT1B neuropathy reveal gain of abnormal Mpz function" First European and North American Charcot-Marie-Tooth Consortium Meeting, CMT type 1B and MPZ (2004)
- "Genetic Nomenclature, Defined Strains and Experimental Design" , Charles River Laboratories/The Jackson laboratory Course, Setting the gold standard in genetics (2004)
- "Genotype, phenotype and mechanism comparisons in transgenic mouse models of hereditary neuropathies" , IBRO Congress (2003)
- "Schwann cell biology: from developmental mechanisms to pathological processes" , IBRO Congress (2003)
- "Transgenic mouse models of hereditary neuropathy" UK Glial Club Meeting (2003)
- "Trangenic mice model diversity in hereditary neuropathies" , European School of Medical Genetics (2002)
- "Proteomics on transgenic optic nerve" Franco-Italian Meeting on MS (2001)
- "Axoglial signals target the myelin basic protein promoter" INSERM, Hopital de la Salpetriere (2000)
- "Epitope tagged-P0 glycoprotein in transgenic mice causes CMT1B-like neuropathy" , Society for Neuroscience (2000)
- "Gain of P0 glycoprotein function: Mouse models of diverse hereditary neuropathies" , University of Edinburgh (2000)
- "Gain of P0 function: Mouse models of hereditary neuropathies" Gordon Conference on Myelin (2000)
- "From stem cells to glia: molecules and mechanisms" UK Glial Cell Club Meeting (2000)
- "P0 overexpression causes congenital hypomyelination in transgenic mice" Telethon Scientific Convention (1999)
- "A distinct axonal signal regulates MBP transcription during CNS myelinogenesis" Society for Neuroscience (1999)
- "Regulation of MBP transcription during CNS myelinogenesis: the role of axons" British Neuroscience Association Meeting (1999)
- "P0 gene dosage and mouse models of CMT1B" Third International Conference on Charcot-Marie-Tooth Disorders (1998)
- "Increased P0 glycoprotein gene dosage causes a dysmyelinating peripheral neuropathy in transgenic mice" Gordon Conference on Myelin (1998)
- "Normal PNS myelination depends on precise dosage of the P0 glycoprotein gene" Armenise-Harvard Symposium (1997)
- "Transgenic mouse model of remyelination" Remyelination in Multiple Sclerosis, European Charcot Foundation Symposium (1996)
- "Normal PNS myelination depends on precise dosage of the P0 glycoprotein gene" Armenise-Harvard Symposium