Lawrence J. Hayward, M.D., Ph.D.

Academic Role: Associate Professor

Faculty Appointment(s) In:
   Neurology

Joint Faculty In:
   Biochemistry and Molecular Pharmacology
   Physiology

Other Affiliation(s):
   Interdisciplinary Graduate Program
   Program in Neuroscience

Motor Neuron Disease Mechanisms

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 laboratory studies genetic forms of ALS using protein chemistry and animal 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 produce toxicity to motor neurons.  In one line of investigation, we have shown that missense substitutions destabilize the enzyme and increase the population of metal-deficient, incompletely folded SOD1.  We hypothesize that these misfolded conformations allow SOD1 to interact aberrantly with other cellular constituents to perturb protein homeostasis or other vital neuronal activities.  My laboratory is also characterizing animal models based on newly identified ALS-related genes so that we can develop novel systems to screen for modulators of motor neuron health and disease progression.

Hyperkalemic Periodic Paralysis: a Muscle Ion Channel Disorder

Ion channels make possible the transmission of electrical signals in nerve and muscle cells by regulating the selective flow of ions (eg. Na⁺, K⁺, Ca²⁺, and Cl^- ) across cellular membranes.  Defective ion channels can produce ‘channelopathy’ phenotypes that include life-threatening arrhythmias, epilepsy, movement disorders, or altered muscle excitability.  My laboratory investigates the physiological consequences of skeletal muscle Na⁺ 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 Na⁺ channels exhibit altered inactivation properties and persistent Na⁺ currents that cause either mild depolarization (which leads to repetitive firing) or severe depolarization (which may cause paralysis by inactivating the majority of normal Na⁺ 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, K⁺-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.

Representative Publications

Periodic Paralysis:

Hayward LJ, Brown RH Jr.  Periodic paralyses and related myotonic diseases.  In: Feldmann E, ed.  Current Diagnosis in Neurology.  St. Louis: Mosby, 1994: 353-56.

Cannon SC, Hayward LJ, Beech J, Brown RH Jr.  Sodium channel inactivation is impaired in equine hyperkalemic periodic paralysis.  J Neurophysiol. 1995 May;73(5):1892-9.

Hayward LJ, Brown RH Jr, 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.  [Commentary]

Hayward LJ, Brown RH Jr, Cannon SC.   Slow inactivation differs among mutant Na channels associated with myotonia and periodic paralysis.  Biophys J. 1997 Mar;72(3):1204-19.

Green DS, Hayward LJ, George AL Jr, 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.

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.  [Commentary]

Hayward LJ.  Techniques for assessing ion channel function in vitro.  In: Rose MR and Griggs RC, ed.  Channelopathies of the Nervous System.  Oxford : Butterworth-Heinemann, 2001: 49-63.

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 1;118(4):1437-49.

Amyotrophic Lateral Sclerosis:

Hayward LJ, Rodriguez JA, Kim JW, Tiwari A, Goto JJ, Cabelli DE, Valentine JS, Brown RH Jr.  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.

Rodriguez JA, Valentine JS, Eggers DK, Roe JA, Tiwari A, Brown RH Jr, 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.

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.

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.

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.

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.

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 USA. 2004 Apr 20;101(16):5976-81.   [Commentary]

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.

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.

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.  [JBC Paper of the Week]

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 USA . 2005 Jul 26;102(30):10516-21.

Tiwari A, Hayward LJ.  Mutant SOD1 instability: implications for toxicity in amyotrophic lateral sclerosis.  Neurodegener Dis. 2005;2(3-4):115-27.

Watanabe S, Nagano S, Duce J, Kiaei M, Li QX, Tucker SM, Tiwari A, Brown RH Jr, 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.

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.

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.

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.

Ström AL, Gal J, Shi P, Kasarskis EJ, Hayward LJ, Zhu H.  Re trograde axonal transport and motor neuron disease.  J Neurochem. 2008 Jul;106(2):495-505.

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.

Potential Rotation Projects

Project #1.  Transgenic animal models of motor neuron degeneration:

Active 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.

Academic Background

Director, Neuromuscular Research Laboratory  

Attending Physician, MDA ALS Center and Neuromuscular Clinic

Office: S5-717
Phone: 508-856-4147
E-mail: Lawrence.Hayward@umassmed.edu
Keywords: Protein Folding, Animal Models of Disease, Neurodegeneration, Motor Neuron Disease, Ion Channels

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