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 Atoh1). 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.