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

 Hayward

Lawrence J. Hayward, M.D., Ph.D.
Faculty page:  http://profiles.umassmed.edu/profiles/ProfileDetails.aspx?From=SE&Person=597
 
My lab investigates the molecular mechanisms of specific inherited neuromuscular disorders, including motor neuron diseases and muscle channelopathies. With expertise in molecular genetics, biochemistry, physiology, and clinical neurology, my group uses in vitro systems, cell cultures, and animal models to discern the functional consequences of these defects. Moreover, we seek to apply the insights gained from these studies toward the development of novel therapies that may ameliorate the underlying pathophysiological disturbances. I evaluate patients with neuromuscular conditions and regularly teach medical students and residents in the neurology clinic. As a research fellow, I identified inactivation defects in mutant skeletal muscle sodium channels that cause hyperkalemic periodic paralysis and later established a knock-in mouse model of this disorder that develops myotonia and a progressive vacuolar myopathy. Over the past 10 years, a major focus of my lab at UMass has been to understand how misfolding of Cu/Zn superoxide dismutase (SOD1) contributes to motor neuron degeneration in amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease). With the recent discovery of ALS-linked mutations in genes associated with RNA metabolism (e.g. TDP-43 and FUS/TLS), my lab is establishing new ALS animal models using both mouse and zebrafish systems. A major objective is to understand how these mutant nucleic acid binding proteins perturb motor neuron homeostasis in response to specific stresses relevant to ALS.

Landmark/Significant papers:

Mutant FUS proteins that cause amyotrophic lateral sclerosis incorporate into stress granules. Bosco DA, Lemay N, Ko HK, Zhou H, Burke C, Kwiatkowski TJ Jr, Sapp P, McKenna-Yasek D, Brown RH Jr, Hayward LJ. Hum Mol Genet. 2010 Nov 1;19(21):4160-75.

Metal deficiency increases aberrant hydrophobicity of mutant superoxide dismutases that cause amyotrophic lateral sclerosis. Tiwari A, Liba A, Sohn SH, Seetharaman SV, Bilsel O, Matthews CR, Hart PJ, Valentine JS, Hayward LJ. J Biol Chem. 2009 Oct 2;284(40):27746-58.

Interaction of amyotrophic lateral sclerosis (ALS)-related mutant copper-zinc superoxide dismutase with the dynein-dynactin complex contributes to inclusion formation. Ström AL, Shi P, Zhang F, Gal J, Kilty R, Hayward LJ, Zhu H. J Biol Chem. 2008 Aug 15;283(33):22795-805.

Targeted mutation of mouse skeletal muscle sodium channel produces myotonia and potassium-sensitive weakness. 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 Jr. J Clin Invest. 2008 Apr;118(4):1437-49.

Interaction between familial amyotrophic lateral sclerosis (ALS)-linked SOD1 mutants and the dynein complex. Zhang F, Ström AL, Fukada K, Lee S, Hayward LJ, Zhu H. J Biol Chem. 2007 Jun 1;282(22):16691-9.

Aberrantly increased hydrophobicity shared by mutants of Cu,Zn-superoxide dismutase in familial amyotrophic lateral sclerosis. Tiwari A, Xu Z, Hayward LJ. J Biol Chem. 2005 Aug 19;280(33):29771-9.
(Selected as Paper of the Week for the August 19, 2005 issue of JBC).

Inhibition of chaperone activity is a shared property of several Cu,Zn-superoxide dismutase mutants that cause amyotrophic lateral sclerosis. Tummala H, Jung C, Tiwari A, Higgins CM, Hayward LJ, Xu Z. J Biol Chem. 2005 May 6;280(18):17725-31.

Amyloid-like filaments and water-filled nanotubes formed by SOD1 mutant proteins linked to familial ALS. Elam JS, Taylor AB, Strange R, Antonyuk S, Doucette PA, Rodriguez JA, Hasnain SS, Hayward LJ, Valentine JS, Yeates TO, Hart PJ. Nat Struct Biol. 2003 Jun;10(6):461-7.

Familial amyotrophic lateral sclerosis mutants of copper/zinc superoxide dismutase are susceptible to disulfide reduction. Tiwari A, Hayward LJ. J Biol Chem. 2003 Feb 21;278(8):5984-92.

Familial amyotrophic lateral sclerosis-associated mutations decrease the thermal stability of distinctly metallated species of human copper/zinc superoxide dismutase. Rodriguez JA, Valentine JS, Eggers DK, Roe JA, Tiwari A, Brown RH Jr, Hayward LJ. J Biol Chem. 2002 May 3;277(18):15932-7.

Decreased metallation and activity in subsets of mutant superoxide dismutases associated with familial amyotrophic lateral sclerosis. Hayward LJ, Rodriguez JA, Kim JW, Tiwari A, Goto JJ, Cabelli DE, Valentine JS, Brown RH Jr. J Biol Chem. 2002 May 3;277(18):15923-31.

Defective slow inactivation of sodium channels contributes to familial periodic paralysis. Hayward LJ, Sandoval GM, Cannon SC. Neurology. 1999 Apr 22;52(7):1447-53.

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

Inactivation defects caused by myotonia-associated mutations in the sodium channel III-IV linker. Hayward LJ, Brown RH Jr, Cannon SC. J Gen Physiol. 1996 May;107(5):559-76.