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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.

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  • X Chromosome Inactivation