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 S5-717

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.