Huda Y. Zoghbi, M.D.
Professor of Molecular and Human Genetics
Director, Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital
Professor, Departments of Pediatrics - Neurology and Developmental Neuroscience, and Neuroscience; Programs in Integrative Molecular and Biomedical Sciences; Developmental Biology; and Translational Biology & Molecular Medicine
Investigator, Howard Hughes Medical Institute
M.D., American University of Beirut/Meharry Medical College, 1979
Postdoc, Baylor College of Medicine, 1985
My laboratory uses genetic, behavioral and cell biological approaches to explore the pathogenesis of polyglutamine neurodegenerative diseases and Rett syndrome, and to study normal neurodevelopment.
Several dominantly inherited spinocerebellar ataxias (SCAs) are caused by expansion of a CAG repeat that encodes glutamine (Q). We discovered that ataxin-1 (ATXN1) with an expanded glutamine tract accumulates in neurons of patients and mouse models of SCA1 and redistributes components of the protein folding and degradation machinery. Surprisingly, genetic studies in Drosophila and mice showed that high levels of even wild-type (WT) ATXN1 can produce effects similar to mutant ATXN1. We hypothesized that ATXN1 exists in alternate conformations, and that the expanded glutamine tract favors a conformation that resists degradation and alters the interactions of ATXN1 with its normal protein partners. With our collaborators, we identified a number of ATXN1 interactors and showed that the expanded polyglutamine tract interferes with the functions of these ATXN1-partner complexes in vivo in various ways. For example, mutant ATXN1 must be in its large native complexes with the transcription repressor Capicua (CIC) to cause neurodegeneration and that decreasing CIC levels by 50% rescues many SCA1 phenotypes in mice (Fryer 2012). Furthermore, we found that partial reduction of ATXN1 levels by mere 20% also rescues several phenotypes (Jafar-Nejad et al., 2011). These data led us to embark on parallel forward genetic screens in human cells and in the Drosophila SCA1 model to identify genes whose inhibition reduces ATXN1 levels and toxicity (Park et al., 2013). The screens identified multiple components of the RAS/MAPK/MSK1 pathway as modulators of ATXN1 levels. The success of this strategy inspired us to employ it to screen for modulators of APP, tau, and α-synuclein proteins, where the protein levels are crucial in the development of Alzheimer and Parkinson diseases, respectively. Beyond these efforts, we are focusing on understanding the in vivo functions of ATXN1, its paralog ATXN1L, and interactors CIC and RBM17 using a combination of genetic studies and molecular analyses.
We discovered that mutations in the X-linked gene encoding methyl CpG-binding protein 2 (MECP2) cause Rett syndrome (Amir, 1999), an incapacitating, progressive postnatal-onset disorder that affects cognitive, language, emotional, and motor skills. We and others have since discovered that MECP2 mutations also underlie autism, various forms of retardation ranging from mild to severe, and even early-onset psychosis. To better understand the role of MeCP2 in Rett pathogenesis, we generated a mouse model using a mutation that causes a typical Rett phenotype in humans, and we also generated mice that overexpress MECP2 at twice the normal levels. The latter mice also develop a progressive neurodevelopmental disorder, which led us back to the clinic to discover a parallel syndrome in human children who have duplications or triplications spanning MECP2.
We next embarked on a series of studies in which we deleted Mecp2 in specific neuronal groups to understand the genesis of different aspects of the wide-ranging Rett phenotype. To our surprise, removing MeCP2 from GABAergic neurons alone reproduced most of the features of RTT, from altered social behavior and seizures to incoordination and stereotyped forepaw movements (Chao, 2010). Interestingly, deletion of Mecp2 in adult mice reproduces all features of the germline deletion mice, including the delayed onset of symptoms and death (McGraw, 2011).
More recently we turned to human data and used genotype-phenotype correlations to identify key functional domains of the protein. The first of theses studies showed MeCP2 is evolutionarily related to HMGA1 protein and that an AT-hook domain in its C-terminus is a key determinant of disease severity (Baker 2013). We are now seeking to understand how MeCP2 affects chromatin architecture, studying the effects of loss or gain of MeCP2 on network activity, and testing therapeutics that enhance GABA signaling in Rett mouse models.
My lab identified Math1 (mouse atonal homolog 1, also known as Atoh1), and showed that it is essential for the genesis of a wide range of cell types, including cerebellar granule neurons, spinal cord interneurons, inner ear hair cells, (Bermingham, 1999), and intestinal secretory (paneth, goblet, and enteroendocrine) cells. Math1 redefines the rhombic lip and its derivations, and Math1-dependent neurons are critical for conscious and unconscious proprioception and for perinatal breathing (Rose, Neuron 2009; Rose, PNAS 2009). In vivo genetic interaction studies identified Math1 as a critical factor for the development of sonic hedgehog induced medulloblastoma (Flora, 2009).
Most recently, we have delineated the role of Math1 in the retrotrapezoid nucleus neurons and the importance of these cells for neonatal respiration and CO2 chemosensitivity. Ongoing studies are focusing on identifying other components of the respiratory hindbrain neurons that are Math1/Atoh1 dependent and on elucidating the molecular functions of Math1 by identifying its interactors and targets in different cellular contexts.
- Park J, Al-Ramahi I, Tan Q, Mollema N, Diaz-Garcia JR, Gallego-Flores T, Lu HC, Lagalwar S, Duvick L, Kang H, Lee Y, Jafar-Nejad P, Sayegh LS, Richman R, Liu X, Gao Y, Shaw CA, Arthur JS, Orr HT, Westbrook TF, Botas J, Zoghbi HY (2013). RAS-MAPK-MSK1 pathway modulates ataxin 1 protein levels and toxicity in SCA1. Nature 498(7454): 325-31. PubMed PMID: 23719381
- Baker SA, Chen L, Wilkins AD, Yu P, Lichtarge O, Zoghbi HY (2013). An AT-hook domain in MeCP2 determines the clinical course of Rett syndrome and related disorders. Cell 152(5):984-960. PubMed PMID: 23452848
- Huang WH, Tupal S, Huang TW, Ward CS, Neul JL, Klisch TJ, Gray PA, Zoghbi HY (2012). Atoh1 Governs the Migration of Postmitotic Neurons that Shape Respiratory Effectiveness at Birth and Chemoresponsiveness in Adulthood. Neuron 75(5): 799-809. PubMed PMID: 22958821
- McGraw CM, Samaco RC, Zoghbi HY (2011). Adult neural function requires MeCP2. Science 333(6039): 186. PubMed PMID: 21636743
- Fryer JD, Yu P, Kang H, Mandel-Brehm C, Carter AN, Crespo-Barreto J, Gao Y, Flora A, Shaw C, Orr HT, Zoghbi HY (2011). Exercise and genetic rescue of SCA1 via the transcriptional repressor Capicua. Science 334(6056): 690-3. PubMed PMID: 22053053
- Chao HT, Chen H, Samaco RC, Chahrour M, Xue M, Yoo J, Neul JL, Gong S, Heintz N, Ekker M, Rubenstein J, Noebels JL, Rosenmund C, Zoghbi HY (2010). GABAergic dysfunction mediates autism-like stereotypies and Rett syndrome phenotypes. Nature 468(7321): 263-9. PubMed PMID: 21068835
- Rose MF, Ahmad K, Thaller C, Zoghbi HY (2009). Excitatory neurons of the proprioceptive, interoceptive, and arousal networks hindbrain networks share a developmental requirement for Math1. Proc. Natl. Acad. Sci. U S A 106(52): 22462-7. PubMed PMID: 20080794
- Flora A, Klisch TJ, Schuster G, Zoghbi HY (2009). Deletion of Atoh1 disrupts sonic hedgehog signaling in the developing cerebellum and prevents medulloblastoma. Science 326(5958): 1424-7. PubMed PMID: 19965762
- Lam YC, Bowman AB, Jafar-Nejad, Lim J, Richman R, Fryer JD, Hyun ED, Duvick LA, Orr HT, Botas J, Zoghbi HY (2006). Mutant ATAXIN-1 interacts with the transcriptional repressor Capicua in its native complex to cause SCA1 neuropathology. Cell 127(7): 1335-47. PubMed PMID: 17190598
- Amir R, Van den Veyver IB, Wan M, Tran C, Francke U, Zoghbi HY (1999). Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat. Genet. 23(2): 185-8. PubMed PMID: 10508514
Awards and Honors
2011: Gruber Prize in Neuroscience
2011: Vita and Lee Lyman Dewey Tuttle Brookwood Legacy Award for Excellence and Partnership in Medicine
2009: Marion Spencer Fay Award, Drexel University College of Medicine, Philadelphia, PA
2009: Cátedra Laboris Professor, University of Monterrey, Monterrey, Mexico
2009: International Rett Syndrome Foundation's Circle of Angels Research Award
2009: Vilcek Prize for Biomedical Research
2008: Honorary Doctorate of Science, Meharry Medical School, TN; Texas Women's Hall of Fame Award Texas Governor's Commission for Women Abilene, TX
2007: Robert J. and Claire Pasarow Foundation Award in Neuropsychiatry, Los Angeles , CA; Honorary Doctorate of Science, Middlebury College, Middlebury, VT
2006: Bristol-Myers Squibb Neuroscience Distinguished Achievement Award
2004: Elected, National Academy of Sciences; Neuronal Plasticity Prize, IPSEN Foundation, Lisbon, Portugal; Marta Philipson Award in Pediatrics, Philipson Foundation for Research, Stockholm, Sweden
2002: Raymond D. Adams Award, American Neurological Association; Elected Fellow, AAAS
2001: Bernard Sachs Award, Child Neurology Society
2000: Elected to the Institute of Medicine, National Academy of Sciences
1998: Sidney Carter Award (American Academy of Neurology); Soriano Award, The American Neurological Association; Javits Award, NINDS Council, National Institutes of Health
1996: E. Mead Johnson Award, Society of Pediatric Research
1995: Kilby Award for Extraordinary Contributions to Society
Huda Y. Zoghbi, M.D.
Howard Hughes Medical Institute
Departments of Pediatrics - Neurology and Developmental Neuroscience, Molecular and Human Genetics, and Neuroscience
Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital
1250 Moursund St., Suite 1350
Houston, TX 77030