Baylor College of Medicine
Dr. Zoghbi is also a professor in the departments of Pediatrics, Molecular and Human Genetics, Neuroscience, and Neurology at Baylor College of Medicine and Director of the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital.
Genetic Studies of Neurodevelopment and Neurodegeneration
Early in Huda Zoghbi’s medical career, encounters with patients motivated her to investigate their enigmatic disorders in the lab. Her research, which combines a search for the root causes of patients’ disorders with basic studies, has led to explanations for several rare neurodegenerative and neurodevelopmental diseases and a broader understanding of neurobiology.
In 1993, Zogbhi’s group, along with Harry Orr’s team at the University of Minnesota, discovered that expansion of CAG repeats in the ATAXIN-1 gene causes the neurodegenerative disease spinocerebellar ataxia type 1 (SCA1). They showed that the polyglutamine tract expansion increases Ataxin-1 protein in neurons, causing toxicity. Through genetic screens in human cells and fruit flies, Zoghbi, Orr, and Baylor colleague Juan Botas found that inhibiting the RAS/MAPK/MSK pathway reduces the levels and toxicity of Ataxin-1. The work suggests a possible strategy for treating SCA1 and for tackling other neurodegenerative disorders caused by toxic protein buildup.
In 1999, Zoghbi’s lab group discovered that mutations in methyl-CpG-binding protein 2 (MECP2) cause Rett syndrome, a crippling, delayed-onset autism spectrum disorder. Her lab has shown MeCP2 is critical for normal function of many diverse neurons and that the brain is very sensitive to MeCP2 levels: doubling MeCP2 levels can cause neurological dysfunction. They revealed that normalizing MeCP2 levels using antisense oligonucleotides reverses MECP2 duplication features in adult mice. This finding provides a potential path for therapeutic intervention and has implications for other duplication disorders.
A foray into fundamental studies of neurodevelopment led Zoghbi to discover a gene called mouse atonal homolog 1 (Math1 or Aoth1). The gene is essential for the genesis of components of the auditory, proprioceptive, and interoceptive systems, as well as secretory cells in the gut and sensory cells in the skin; it is also involved in the development of neurons critical for neonatal breathing and response to CO2. Her team is now dissecting Atoh1’s molecular functions and its role in regulating breathing.
Grants from the National Institutes of Health and Rett Syndrome Research Trust provided partial support for these projects.
Huda 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.