Dr. Zoghbi and her collaborators have unraveled the genetic underpinnings of a number of devastating neurological disorders, including Rett syndrome and spinocerebellar ataxia type 1 (SCA1). Their discoveries have provided new ways of thinking about more common neurological disorders, including autism, intellectual disability, and Parkinson’s disease, and could lead to better treatments.
Zoghbi enrolled in medical school at American University in Beirut in 1975, just before war erupted in Lebanon. After her first year, she went home to her family’s house in Lebanon, intending to return to school in the fall. But Zoghbi’s parents decided to send her and her brothers to stay with relatives in the United States after her brother was hit by a piece of shrapnel and sustained a minor injury. She was able to finish her medical training at Meharry Medical College, in Nashville, Tennessee.
Zoghbi soon found herself drawn to disorders that affect the brain. “Neurology grabbed me because of how logical it is,” she says. “You observe the patient, analyze her symptoms, and work backward to figure out exactly which part of the brain is responsible for the problem.” In her second year of residency, Zoghbi encountered a puzzling case – a young girl who was healthy until around the age of two, when she stopped making eye contact, shied away from social interactions, ceased to communicate, and started obsessively wringing her hands. Zoghbi set out to determine what caused the girl’s sudden neurological deterioration.
Sixteen years later, Zoghbi’s lab group identified MECP2, the gene responsible for Rett syndrome. Children afflicted with this rare neurodevelopmental disorder develop normally for 6 to 18 months and then regress: they lose language and motor skills, and develop stereotypic movements such as hand-wringing or hand-flapping. MECP2, Zoghbi found, encodes a protein that is critical for the normal functioning of mature neurons in the brain; the protein is produced when nerve cells are forming connections as a child interacts with the world. Rett syndrome occurs primarily in girls, because boys who inherit an inactive form of MECP2 – which lies on the X chromosome – usually die shortly after birth. Girls survive because, having two X chromosomes, they stand a good chance of inheriting a healthy copy of the gene.
Zoghbi and her colleagues have also identified the mutation responsible for SCA1, one of several polyglutamine neurodegenerative disorders that slowly rob their victims of balance and motor control. The culprit is a genetic stutter that slightly increases the size of the SCA1 gene, causing the product of the mutant gene – a protein called Ataxin-1 – to become large and misshapen, unable to interact normally with its usual partners. Polyglutamine diseases are part of a larger class of neurodegenerative diseases known as proteinopathies, which include Parkinson’s and Alzheimer’s disease. Zoghbi’s work on the pathogenic mechanisms of polyglutamine proteinopathies has proven relevant to this larger class of disorders. Her lab team is searching for compounds that enhance the clearance of mutant proteins in several of these diseases, which might slow disease progression or prevent it altogether.