Section: Research

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.

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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