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    Lawrence J Hayward MD, PhD

    TitleProfessor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentNeurology
    AddressUniversity of Massachusetts Medical School
    55 Lake Avenue North
    Worcester MA 01655
    Phone508-856-4147
      Other Positions
      InstitutionUMMS - School of Medicine
      DepartmentBiochemistry and Molecular Pharmacology

      InstitutionUMMS - School of Medicine
      DepartmentCell and Developmental Biology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentCell Biology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentInterdisciplinary Graduate Program

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentMD/PhD Program

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentNeuroscience

        Overview 
        Narrative

        Biography

        Lawrence Hayward received his B.S. in Electrical Engineering from Washington University in St. Louis in 1982. His doctoral training in the laboratory of Robert J. Schwartz focused on neuroscience and developmental gene regulation in muscle, and he completed the M.D.–Ph.D. program at Baylor College of Medicine in 1989. From 1990-93, he was a neurology resident at Massachusetts General Hospital (MGH). As a Howard Hughes Medical Institute postdoctoral fellow from 1994-97 in the laboratories of Robert H. Brown, Jr. and Stephen Cannon at MGH, he identified functional defects in mutant sodium channels that cause hyperkalemic periodic paralysis. In 1998, he initiated biochemical studies to detect toxic properties of mutant superoxide dismutase (SOD1) enzymes that cause familial amyotrophic lateral sclerosis (ALS). Dr. Hayward joined the faculty of UMass Medical School and started his laboratory in the Neurology Department in 2000. He sees patients regularly in the neuromuscular clinic, teaches medical students and residents on the wards, and mentors graduate students and fellows in the laboratory. Dr. Hayward is a member of the UMass Neurotherapeutics Institute, the ALS Therapy Alliance, and the SOD1-ALS (ICOSA) research consortium.

        Office: Room AS6-1045

        Research Interests

        Misfolding of Mutant SOD1 Variants in ALS

        Amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease) is a neurodegenerative disorder that causes preferential loss of motor neurons in the brain and spinal cord. Symptoms of weakness and spasticity typically strike patients during middle age and progressively worsen until death occurs from respiratory paralysis. My lab studies genetic forms of ALS using animal and cellular models to gain insights regarding motor neuron vulnerabilities and pathophysiological mechanisms. Understanding why motor neurons die in these models may help us to develop effective therapies for the more common sporadic forms of ALS and related motor neuron diseases.

        A subset of familial ALS is caused by mutations in the gene encoding Cu, Zn superoxide dismutase (SOD1), an abundant antioxidant enzyme that in mutant forms can become toxic to motor neurons. We have shown that missense substitutions destabilize the enzyme and increase the population of metal-deficient, incompletely folded SOD1. We are investigating how these misfolded conformations allow SOD1 to interact aberrantly with other cellular constituents to perturb protein homeostasis or other vital neuronal activities.

        Mouse and Zebrafish Models of Motor Neuron Disease

        With the recent discovery of ALS-linked mutations in genes associated with RNA processing and metabolism (e.g. TDP-43 and FUS/TLS), my lab is establishing new ALS animal models using both mouse and zebrafish systems. These complementary systems allow us to manipulate the expression of ALS mutants both acutely and chronically in relevant tissues. We can then evaluate the molecular, cellular, and behavioral consequences in vivo or in primary cell cultures. Our objectives are to understand how these mutant nucleic acid binding proteins perturb motor neuron homeostasis in response to stresses or aging and to use these models to screen for novel ALS therapeutic agents.

        Progressive Vacuolar Myopathy in Hyperkalemic Periodic Paralysis

        Ion channels make possible the transmission of electrical signals in nerve and muscle cells by regulating the selective flow of ions across cellular membranes. Defective ion channels can produce ‘channelopathy’ phenotypes that include life-threatening arrhythmias, epilepsy, movement disorders, or altered muscle excitability. My lab investigates the physiological consequences of skeletal muscle sodium channel mutations responsible for hyperkalemic periodic paralysis (HyperKPP). Affected individuals experience attacks of muscle stiffness, weakness, or paralysis triggered by elevated serum potassium, rest after exercise, or muscle cooling.

        HyperKPP mutant sodium channels exhibit altered inactivation properties and persistent sodium currents that cause either mild depolarization (which leads to repetitive firing) or severe depolarization (which may cause paralysis by inactivating the majority of normal sodium channels). We have developed a knock-in mouse model corresponding to the HyperKPP Met-1592-Val variant that reproduces many features of the disease, including myotonia, potassium-sensitive weakness, and development of a slowly progressive vacuolar myopathy. Ongoing experiments are addressing specific mechanisms related to attack triggers and the myopathic process so that improved therapies may be developed for HyperKPP and related myopathies.

         



        Rotation Projects

        Rotation Projects

        Project #1.  Mouse and zebrafish models of motor neuron disease:

        Projects include the development and characterization of novel in vivo models relevant to amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease) and related motor neuron diseases.  This project will provide the student with familiarity in the design and analysis of models using mouse or zebrafish systems.  Depending on the length of the rotation, opportunities for phenotypic analysis of transgenic animals can be tailored to student interest.  Techniques employed include fluorescence imaging, electrophysiology, biochemistry, and behavioral analysis.

        Project #2.  Misfolding of mutant Cu,Zn superoxide dismutase (SOD1) in ALS

        More than 100 distinct missense mutations have been identified in the gene encoding SOD1 in families with inherited forms of ALS.  A consensus is emerging that these mutant residues increase the propensity of the nascent enzyme to populate folding intermediate conformations that may cause toxicity to motor neurons.  We are interested in defining structural aspects of the misfolded proteins and their potential interactions with other cellular constituents.  Rotation projects are available in which the student will apply biochemical methods, mass spectrometry, and fluorescence imaging to characterize the consequences of SOD1 misfolding in cellular systems.

        Project #3.   Physiology of periodic paralysis: 

        Hyperkalemic periodic paralysis is a muscle disorder characterized by attacks of weakness or muscle stiffness (myotonia) that can be triggered by exercise or potassium ingestion.   We have developed a knock-in mouse model of this disorder in which the Met-1592-Val mutant Na channel is expressed in muscle.  We are interested to study the physiological triggers of attacks in these animals and the basis for the occurrence of myopathic changes with aging.



        Bibliographic 
        selected publications
        List All   |   Timeline
        1. Morfini GA, Bosco DA, Brown H, Gatto R, Kaminska A, Song Y, Molla L, Baker L, Marangoni MN, Berth S, Tavassoli E, Bagnato C, Tiwari A, Hayward LJ, Pigino GF, Watterson DM, Huang CF, Banker G, Brown RH, Brady ST. Inhibition of Fast Axonal Transport by Pathogenic SOD1 Involves Activation of p38 MAP Kinase. PLoS One. 2013; 8(6):e65235.
          View in: PubMed
        2. Convertini P, Zhang J, de la Grange P, Hayward LJ, Zhu H, Stamm S. Genome wide array analysis indicates that an amyotrophic lateral sclerosis mutation of FUS causes an early increase of CAMK2N2 in vitro. Biochim Biophys Acta. 2013 Aug; 1832(8):1129-35.
          View in: PubMed
        3. Renaud JM, Hayward LJ. Lessons learned from muscle fatigue: implications for treatment of patients with hyperkalemic periodic paralysis. Recent Pat Biotechnol. 2012 Dec 1; 6(3):184-91.
          View in: PubMed
        4. Clausen T, Nielsen OB, Clausen JD, Pedersen TH, Hayward LJ. Na+,K+-pump stimulation improves contractility in isolated muscles of mice with hyperkalemic periodic paralysis. J Gen Physiol. 2011 Jul; 138(1):117-30.
          View in: PubMed
        5. Ju S, Tardiff DF, Han H, Divya K, Zhong Q, Maquat LE, Bosco DA, Hayward LJ, Brown RH, Lindquist S, Ringe D, Petsko GA. A Yeast Model of FUS/TLS-Dependent Cytotoxicity. PLoS Biol. 2011 Apr; 9(4):e1001052.
          View in: PubMed
        6. Bosco DA, Lemay N, Ko HK, Zhou H, Burke C, Kwiatkowski TJ, Sapp P, McKenna-Yasek D, Brown RH, Hayward LJ. Mutant FUS proteins that cause amyotrophic lateral sclerosis incorporate into stress granules. Hum Mol Genet. 2010 Nov 1; 19(21):4160-75.
          View in: PubMed
        7. Morfini GA, Burns M, Binder LI, Kanaan NM, LaPointe N, Bosco DA, Brown RH, Brown H, Tiwari A, Hayward L, Edgar J, Nave KA, Garberrn J, Atagi Y, Song Y, Pigino G, Brady ST. Axonal transport defects in neurodegenerative diseases. J Neurosci. 2009 Oct 14; 29(41):12776-86.
          View in: PubMed
        8. Tiwari A, Liba A, Sohn SH, Seetharaman SV, Bilsel O, Matthews CR, Hart PJ, Valentine JS, Hayward LJ. Metal deficiency increases aberrant hydrophobicity of mutant superoxide dismutases that cause amyotrophic lateral sclerosis. J Biol Chem. 2009 Oct 2; 284(40):27746-58.
          View in: PubMed
        9. Molnar KS, Karabacak NM, Johnson JL, Wang Q, Tiwari A, Hayward LJ, Coales SJ, Hamuro Y, Agar JN. A common property of amyotrophic lateral sclerosis-associated variants: destabilization of the copper/zinc superoxide dismutase electrostatic loop. J Biol Chem. 2009 Nov 6; 284(45):30965-73.
          View in: PubMed
        10. Karabacak NM, Li L, Tiwari A, Hayward LJ, Hong P, Easterling ML, Agar JN. Sensitive and specific identification of wild type and variant proteins from 8 to 669 kDa using top-down mass spectrometry. Mol Cell Proteomics. 2009 Apr; 8(4):846-56.
          View in: PubMed
        11. Ström AL, Shi P, Zhang F, Gal J, Kilty R, Hayward LJ, Zhu H. Interaction of amyotrophic lateral sclerosis (ALS)-related mutant copper-zinc superoxide dismutase with the dynein-dynactin complex contributes to inclusion formation. J Biol Chem. 2008 Aug 15; 283(33):22795-805.
          View in: PubMed
        12. Ström AL, Gal J, Shi P, Kasarskis EJ, Hayward LJ, Zhu H. Retrograde axonal transport and motor neuron disease. J Neurochem. 2008 Jul; 106(2):495-505.
          View in: PubMed
        13. Hayward LJ, Kim JS, Lee MY, Zhou H, Kim JW, Misra K, Salajegheh M, Wu FF, Matsuda C, Reid V, Cros D, Hoffman EP, Renaud JM, Cannon SC, Brown RH. Targeted mutation of mouse skeletal muscle sodium channel produces myotonia and potassium-sensitive weakness. J Clin Invest. 2008 Apr; 118(4):1437-49.
          View in: PubMed
        14. Cao X, Antonyuk SV, Seetharaman SV, Whitson LJ, Taylor AB, Holloway SP, Strange RW, Doucette PA, Valentine JS, Tiwari A, Hayward LJ, Padua S, Cohlberg JA, Hasnain SS, Hart PJ. Structures of the G85R variant of SOD1 in familial amyotrophic lateral sclerosis. J Biol Chem. 2008 Jun 6; 283(23):16169-77.
          View in: PubMed
        15. Shaw BF, Lelie HL, Durazo A, Nersissian AM, Xu G, Chan PK, Gralla EB, Tiwari A, Hayward LJ, Borchelt DR, Valentine JS, Whitelegge JP. Detergent-insoluble aggregates associated with amyotrophic lateral sclerosis in transgenic mice contain primarily full-length, unmodified superoxide dismutase-1. J Biol Chem. 2008 Mar 28; 283(13):8340-50.
          View in: PubMed
        16. Zhang F, Ström AL, Fukada K, Lee S, Hayward LJ, Zhu H. Interaction between familial amyotrophic lateral sclerosis (ALS)-linked SOD1 mutants and the dynein complex. J Biol Chem. 2007 Jun 1; 282(22):16691-9.
          View in: PubMed
        17. Watanabe S, Nagano S, Duce J, Kiaei M, Li QX, Tucker SM, Tiwari A, Brown RH, Beal MF, Hayward LJ, Culotta VC, Yoshihara S, Sakoda S, Bush AI. Increased affinity for copper mediated by cysteine 111 in forms of mutant superoxide dismutase 1 linked to amyotrophic lateral sclerosis. Free Radic Biol Med. 2007 May 15; 42(10):1534-42.
          View in: PubMed
        18. Rodriguez JA, Shaw BF, Durazo A, Sohn SH, Doucette PA, Nersissian AM, Faull KF, Eggers DK, Tiwari A, Hayward LJ, Valentine JS. Destabilization of apoprotein is insufficient to explain Cu,Zn-superoxide dismutase-linked ALS pathogenesis. Proc Natl Acad Sci U S A. 2005 Jul 26; 102(30):10516-21.
          View in: PubMed
        19. Tiwari A, Xu Z, Hayward LJ. Aberrantly increased hydrophobicity shared by mutants of Cu,Zn-superoxide dismutase in familial amyotrophic lateral sclerosis. J Biol Chem. 2005 Aug 19; 280(33):29771-9.
          View in: PubMed
        20. Antonyuk S, Elam JS, Hough MA, Strange RW, Doucette PA, Rodriguez JA, Hayward LJ, Valentine JS, Hart PJ, Hasnain SS. Structural consequences of the familial amyotrophic lateral sclerosis SOD1 mutant His46Arg. Protein Sci. 2005 May; 14(5):1201-13.
          View in: PubMed
        21. Tummala H, Jung C, Tiwari A, Higgins CM, Hayward LJ, Xu Z. Inhibition of chaperone activity is a shared property of several Cu,Zn-superoxide dismutase mutants that cause amyotrophic lateral sclerosis. J Biol Chem. 2005 May 6; 280(18):17725-31.
          View in: PubMed
        22. Tiwari A, Hayward LJ. Mutant SOD1 instability: implications for toxicity in amyotrophic lateral sclerosis. Neurodegener Dis. 2005; 2(3-4):115-27.
          View in: PubMed
        23. Chacko BM, Qin BY, Tiwari A, Shi G, Lam S, Hayward LJ, De Caestecker M, Lin K. Structural basis of heteromeric smad protein assembly in TGF-beta signaling. Mol Cell. 2004 Sep 10; 15(5):813-23.
          View in: PubMed
        24. Hough MA, Grossmann JG, Antonyuk SV, Strange RW, Doucette PA, Rodriguez JA, Whitson LJ, Hart PJ, Hayward LJ, Valentine JS, Hasnain SS. Dimer destabilization in superoxide dismutase may result in disease-causing properties: structures of motor neuron disease mutants. Proc Natl Acad Sci U S A. 2004 Apr 20; 101(16):5976-81.
          View in: PubMed
        25. Elam JS, Taylor AB, Strange R, Antonyuk S, Doucette PA, Rodriguez JA, Hasnain SS, Hayward LJ, Valentine JS, Yeates TO, Hart PJ. Amyloid-like filaments and water-filled nanotubes formed by SOD1 mutant proteins linked to familial ALS. Nat Struct Biol. 2003 Jun; 10(6):461-7.
          View in: PubMed
        26. Strange RW, Antonyuk S, Hough MA, Doucette PA, Rodriguez JA, Hart PJ, Hayward LJ, Valentine JS, Hasnain SS. The structure of holo and metal-deficient wild-type human Cu, Zn superoxide dismutase and its relevance to familial amyotrophic lateral sclerosis. J Mol Biol. 2003 May 9; 328(4):877-91.
          View in: PubMed
        27. Elam JS, Malek K, Rodriguez JA, Doucette PA, Taylor AB, Hayward LJ, Cabelli DE, Valentine JS, Hart PJ. An alternative mechanism of bicarbonate-mediated peroxidation by copper-zinc superoxide dismutase: rates enhanced via proposed enzyme-associated peroxycarbonate intermediate. J Biol Chem. 2003 Jun 6; 278(23):21032-9.
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        28. Tiwari A, Hayward LJ. Familial amyotrophic lateral sclerosis mutants of copper/zinc superoxide dismutase are susceptible to disulfide reduction. J Biol Chem. 2003 Feb 21; 278(8):5984-92.
          View in: PubMed
        29. Rodriguez JA, Valentine JS, Eggers DK, Roe JA, Tiwari A, Brown RH, Hayward LJ. Familial amyotrophic lateral sclerosis-associated mutations decrease the thermal stability of distinctly metallated species of human copper/zinc superoxide dismutase. J Biol Chem. 2002 May 3; 277(18):15932-7.
          View in: PubMed
        30. Hayward LJ, Rodriguez JA, Kim JW, Tiwari A, Goto JJ, Cabelli DE, Valentine JS, Brown RH. Decreased metallation and activity in subsets of mutant superoxide dismutases associated with familial amyotrophic lateral sclerosis. J Biol Chem. 2002 May 3; 277(18):15923-31.
          View in: PubMed
        31. Hayward LJ, Sandoval GM, Cannon SC. Defective slow inactivation of sodium channels contributes to familial periodic paralysis. Neurology. 1999 Apr 22; 52(7):1447-53.
          View in: PubMed
        32. Andreu AL, Bruno C, Shanske S, Shtilbans A, Hirano M, Krishna S, Hayward L, Systrom DS, Brown RH, DiMauro S. Missense mutation in the mtDNA cytochrome b gene in a patient with myopathy. Neurology. 1998 Nov; 51(5):1444-7.
          View in: PubMed
        33. Green DS, Hayward LJ, George AL, Cannon SC. A proposed mutation, Val781Ile, associated with hyperkalemic periodic paralysis and cardiac dysrhythmia is a benign polymorphism. Ann Neurol. 1997 Aug; 42(2):253-6.
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        34. Hayward LJ, Brown RH, Cannon SC. Slow inactivation differs among mutant Na channels associated with myotonia and periodic paralysis. Biophys J. 1997 Mar; 72(3):1204-19.
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        35. Hosler BA, Nicholson GA, Sapp PC, Chin W, Orrell RW, de Belleroche JS, Esteban J, Hayward LJ, Mckenna-Yasek D, Yeung L, Cherryson AK, Dench JE, Wilton SD, Laing NG, Horvitz HR, Brown RH. Three novel mutations and two variants in the gene for Cu/Zn superoxide dismutase in familial amyotrophic lateral sclerosis. Neuromuscul Disord. 1996 Oct; 6(5):361-6.
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        36. Hayward LJ, Brown RH, Cannon SC. Inactivation defects caused by myotonia-associated mutations in the sodium channel III-IV linker. J Gen Physiol. 1996 May; 107(5):559-76.
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        37. Cannon SC, Hayward LJ, Beech J, Brown RH. Sodium channel inactivation is impaired in equine hyperkalemic periodic paralysis. J Neurophysiol. 1995 May; 73(5):1892-9.
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        38. Hayward LJ, Zhu YY, Schwartz RJ. Cellular localization of muscle and nonmuscle actin mRNAs in chicken primary myogenic cultures: the induction of alpha-skeletal actin mRNA is regulated independently of alpha-cardiac actin gene expression. J Cell Biol. 1988 Jun; 106(6):2077-86.
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        39. Hayward LJ, Schwartz RJ. Sequential expression of chicken actin genes during myogenesis. J Cell Biol. 1986 Apr; 102(4):1485-93.
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