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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
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    Other Positions
    InstitutionUMMS - School of Medicine
    DepartmentBiochemistry and Molecular Pharmacology

    InstitutionUMMS - School of Medicine
    DepartmentNeurology

    InstitutionUMMS - School of Medicine
    DepartmentNeuroNexus Institute

    InstitutionUMMS - School of Medicine
    DepartmentRadiology

    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


    Collapse Biography 
    Collapse education and training
    Washington University, Saint Louis, MO, United StatesBSElectrical Engineering
    Baylor College of Medicine, Houston, TX, United StatesMD
    Baylor College of Medicine, Houston, TX, United StatesPHDNeuroscience

    Collapse Overview 
    Collapse overview

    Academic Background


    Lawrence Hayward investigated gene regulatory mechanisms in developing skeletal muscle in the laboratory of Robert J. Schwartz and completed the M.D.-Ph.D. Program at Baylor College of Medicine in 1989. He served as a resident in Neurology at Massachusetts General Hospital (MGH) during 1990-93. Dr. Hayward continued at MGH as a Muscular Dystrophy Association postdoctoral fellow and a Howard Hughes Medical Institute neuromuscular research and clinical fellow from 1994-97. His postdoctoral research with Robert H. Brown, Jr. and Stephen Cannon focused upon how defective ion channels in periodic paralysis cause abnormal muscle cell firing, which triggers attacks of weakness and progressive muscle damage. In 1998, with support from the ALS Association as an Instructor in Neurology at Harvard Medical School, he initiated biochemical and biophysical studies of misfolded mutant superoxide dismutase (SOD1) enzymes that cause ALS (amyotrophic lateral sclerosis). In 2000, Dr. Hayward joined the Neurology Department at the University of Massachusetts Medical School, where he is now a Professor of Neurology.


    Office: Room AS6-1045


    FSH Muscular Dystrophy Clinic
    Appointments: (508) 334-2527


    Research Interests


    I am a physician-scientist providing care since 2000 for patients in the UMMS MDA Neuromuscular Clinic and serve as Co-Director of the multidisciplinary FSH Muscular Dystrophy Clinic. My research group focuses on defining molecular mechanisms that cause selected neuromuscular diseases, including ALS (amyotrophic lateral sclerosis), FSH (facioscapulohumeral) muscular dystrophy, and hyperkalemic periodic paralysis. Our objective is to direct this knowledge toward designing more effective treatments for our patients with these conditions. My laboratory applies expertise in basic muscle biology, cellular and animal modeling, gene regulation, protein biochemistry, and ion channel physiology to understand how genetic changes and environmental influences trigger various pathological responses in these diseases. We collaborate closely with other researchers in the UMMS Wellstone Center for FSHD and the UMMS Neurotherapeutics Institute.


    Cellular and Animal Models of 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. Mutant variants of nuclear proteins involved in gene transcription and RNA processing such as TDP-43 and FUS/TLS cause hereditary ALS by unclear mechanisms. My lab has established new ALS models to study the consequences of these altered genes using cell cultures, zebrafish, and genetically engineered mice. Our group showed that some ALS-linked FUS/TLS mutants localize abnormally to the cytoplasm, where they can incorporate reversibly into stress granules. Other FUS/TLS mutants remain mostly nuclear but can perturb the dynamics of nuclear bodies that may be important for stress signaling and protein recycling inside the nucleus. We are interested to understand the significance of these perturbations to cellular homeostasis in ALS using transgenic and knock-in mouse models, CNS cells edited using CRISPR-Cas9 methodology, and primary cells from ALS patients. We are developing assays to screen for agents that correct these perturbations and thereby may protect motor neurons in ALS.


    FSH Muscular Dystrophy


    Facioscapulohumeral (FSH) muscular dystrophy is the second most common adult-onset muscular dystrophy and typically presents with weakness of the facial muscles, scapular region, and arms. While symptoms usually become apparent in late adolescence, the onset and severity can be quite variable, and frequently the leg muscles also become affected, leading to impaired mobility. Progressive hearing and vision impairment can add to the disability, and at present, there are no effective treatments for this relentless disease.
    Genetic studies in FSHD have identified a loss of 3.3 kb repetitive sequence units known as D4Z4 repeats on chromosome 4q; normal individuals can have >100 D4Z4 repeats, while those affected with FSHD have only 1-10 units. A major consequence of the deletion of D4Z4 units, which are thought to act epigenetically to repress the expression of neighboring genes, is the inappropriate expression of a powerful developmental transcription factor, DUX4. Even transient mis-expression of DUX4 in mature muscle has profound consequences due to propagated activation of a variety of cytotoxic target genes that contribute to the injurious FSHD phenotype.
    My group is enrolling FSHD patients from our multidisciplinary FSH Muscular Dystrophy Clinic into a biomarker and longitudinal analysis study in collaboration with the UMMS Wellstone Center for FSHD. We will follow these patients over time with clinical examinations including muscle strength assessment, MRI analyses of selected muscles, and blood and tissue samples to determine how gene expression changes correlate with disease progression. We aim to develop informative models of FSHD so that we can accelerate the translation of research results into new therapies for our FSHD patient population.


    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.




    Collapse Bibliographic 
    Collapse selected publications
    Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
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    1. Didiot MC, Ferguson CM, Ly S, Coles AH, Smith AO, Bicknell AA, Hall LM, Sapp E, Echeverria D, Pai AA, DiFiglia M, Moore MJ, Hayward LJ, Aronin N, Khvorova A. Nuclear Localization of Huntingtin mRNA Is Specific to Cells of Neuronal Origin. Cell Rep. 2018 Sep 04; 24(10):2553-2560.e5. PMID: 30184490.
      View in: PubMed
    2. Gal J, Kuang L, Barnett KR, Zhu BZ, Shissler SC, Korotkov KV, Hayward LJ, Kasarskis EJ, Zhu H. ALS mutant SOD1 interacts with G3BP1 and affects stress granule dynamics. Acta Neuropathol. 2016 Oct; 132(4):563-76. PMID: 27481264.
      View in: PubMed
    3. Khogali S, Lucas B, Ammar T, Dejong D, Barbalinardo M, Hayward LJ, Renaud JM. Physiological basis for muscle stiffness and weakness in a knock-in M1592V mouse model of hyperkalemic periodic paralysis. Physiol Rep. 2015 Dec; 3(12). PMID: 26702073.
      View in: PubMed
    4. Ammar T, Lin W, Higgins A, Hayward LJ, Renaud JM. Understanding the physiology of the asymptomatic diaphragm of the M1592V hyperkalemic periodic paralysis mouse. J Gen Physiol. 2015 Dec; 146(6):509-25. PMID: 26621775.
      View in: PubMed
    5. Tibshirani M, Tradewell ML, Mattina KR, Minotti S, Yang W, Zhou H, Strong MJ, Hayward LJ, Durham HD. Cytoplasmic sequestration of FUS/TLS associated with ALS alters histone marks through loss of nuclear protein arginine methyltransferase 1. Hum Mol Genet. 2015 Feb 1; 24(3):773-86. PMID: 25274782.
      View in: PubMed
    6. Lucas B, Ammar T, Khogali S, DeJong D, Barbalinardo M, Nishi C, Hayward LJ, Renaud JM. Contractile abnormalities of mouse muscles expressing hyperkalemic periodic paralysis mutant NaV1.4 channels do not correlate with Na+ influx or channel content. Physiol Genomics. 2014 Jun 1; 46(11):385-97. PMID: 24714718.
      View in: PubMed
    7. 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. PMID: 23776455.
      View in: PubMed
    8. 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. PMID: 23545117.
      View in: PubMed
    9. Renaud JM, Hayward LJ. Lessons learned from muscle fatigue: implications for treatment of patients with hyperkalemic periodic paralysis. Recent Pat Biotechnol. 2012 Dec; 6(3):184-91. PMID: 23092434.
      View in: PubMed
    10. 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. PMID: 21708955.
      View in: PubMed
    11. 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. PMID: 21541368.
      View in: PubMed
    12. 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. PMID: 20699327.
      View in: PubMed
    13. 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. PMID: 19828789.
      View in: PubMed
    14. 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 02; 284(40):27746-58. PMID: 19651777.
      View in: PubMed
    15. 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. PMID: 19635794.
      View in: PubMed
    16. 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. PMID: 19074999.
      View in: PubMed
    17. 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. PMID: 18515363.
      View in: PubMed
    18. 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. PMID: 18384644.
      View in: PubMed
    19. 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. PMID: 18317596.
      View in: PubMed
    20. 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. PMID: 18378676.
      View in: PubMed
    21. 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. PMID: 18192269.
      View in: PubMed
    22. 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. PMID: 17403682.
      View in: PubMed
    23. 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. PMID: 17448900.
      View in: PubMed
    24. 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. PMID: 16020530.
      View in: PubMed
    25. 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. PMID: 15958382.
      View in: PubMed
    26. 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. PMID: 15840828.
      View in: PubMed
    27. 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. PMID: 15753080.
      View in: PubMed
    28. Tiwari A, Hayward LJ. Mutant SOD1 instability: implications for toxicity in amyotrophic lateral sclerosis. Neurodegener Dis. 2005; 2(3-4):115-27. PMID: 16909016.
      View in: PubMed
    29. 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. PMID: 15350224.
      View in: PubMed
    30. 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. PMID: 15056757.
      View in: PubMed
    31. 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. PMID: 12754496.
      View in: PubMed
    32. 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. PMID: 12729761.
      View in: PubMed
    33. 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. PMID: 12649272.
      View in: PubMed
    34. 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. PMID: 12458194.
      View in: PubMed
    35. 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. PMID: 11854285.
      View in: PubMed
    36. 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. PMID: 11854284.
      View in: PubMed
    37. 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. PMID: 10227633.
      View in: PubMed
    38. 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. PMID: 9818877.
      View in: PubMed
    39. 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. PMID: 9266738.
      View in: PubMed
    40. 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. PMID: 9138567.
      View in: PubMed
    41. 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. PMID: 8938700.
      View in: PubMed
    42. 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. PMID: 8740371.
      View in: PubMed
    43. 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. PMID: 7623088.
      View in: PubMed
    44. 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. PMID: 3384853.
      View in: PubMed
    45. Hayward LJ, Schwartz RJ. Sequential expression of chicken actin genes during myogenesis. J Cell Biol. 1986 Apr; 102(4):1485-93. PMID: 3007534.
      View in: PubMed
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