Huda Y. Zoghbi, M.D., Director
Director, Duncan Neurological Research Institute
Ralph D. Feigin, M.D., Endowed Chair
Distinguished Service Professor, Baylor College of Medicine
Investigator, Howard Hughes Medical Institute
Member, American Academy of Arts and Sciences, National Academy of Medicine and National Academy of Sciences
Research focus: Triplet repeat diseases (Spinocerebellar ataxia types 1 and 7), Alzheimer's and Parkinson's diseases, Rett syndrome, MECP2 duplication syndrome, and autism.
There are four major research projects in the Zoghbi lab. The first began with the discovery (in collaboration with Dr. Harry Orr) of the dynamic mutation underlying Spinocerebellar ataxia type 1 (SCA1), a late-onset disease caused by expansion of a CAG repeat that encodes glutamine in Ataxin-1. Rigorous use of SCA1 mouse models has revealed the roles of protein misfolding and altered interactions with protein partners in SCA1 pathogenesis. We determined that interaction of polyglutamine-expanded Ataxin-1 with Capicua drives Purkinje cell degeneration, but to our surprise, we learned that Capicua is one of several interactors driving SCA1 pathogenesis. We also learned that reduction of polyglutamine-expanded Ataxin-1 rescues SCA1 phenotypes. We are now focused on revealing the repertoire of Ataxin-1 interactors that drive regional vulnerability and are pursuing therapeutic strategies that lower Ataxin-1.
Inspired by our work on SCA1 we rationalized that mild to moderate reduction of the disease-driving proteins tau and a-synuclein will help protect the brain in Alzheimer disease (AD) and Parkinson disease (PD), respectively. To this end, we collaborated with Dr. Juan Botas and carried out cross-species genetic screens to identify post-translational regulators of tau and a-synuclein. Recently, we identified potentially druggable targets that are critical for the degradation of tau. In addition, we are generating new mouse models for PD to gain insight into how a-synuclein drives pathogenesis.
A major project sprang from the lab’s discovery that mutations in MECP2 form the genetic basis of Rett syndrome, a devastating childhood illness that appears after a period of apparently normal development, robbing girls of acquired language and motor skills and causing a host of other difficulties, including gastrointestinal problems, anxiety, and certain autistic features. Studies of the pathogenesis of Rett syndrome are beginning to provide insight into epigenetic modulation of neuronal function.
Beyond Rett syndrome we learned that duplications spanning MECP2 cause a severe and progressive neurological disorder. Using an animal model for this disorder, we showed that antisense oligonucleotide treatment in adult animals can normalize MECP2 levels and reverse the features of the disorder providing the proof of concept data to chart the path to clinical trials. We also discovered that enhancing the activity of neuronal circuits in Rett mouse model either through deep brain stimulation) or intensive training in the pre-symptomatic stage rescues Rett-like phenotypes. We are now pursuing molecular studies to identify the molecular mechanism driving such rescue. In complementary studies, we are performing genetic screens to identify regulators of MeCP2 levels as such regulators can teach us about MeCP2 biology and regulation and provide potential therapeutic targets to modulate MeCP2 levels in Rett syndrome and MeCP2 duplication disorder.
A new line of research is dedicated to identifying genetic causes of autism spectrum disorder (ASDs) with specific attention to the genetic factors that might drive the male sex bias. This project is part of a collaborative effort with Drs. Aravinda Chakravarti, Evan Eichler, and Thomas Nowakowski and is funded by SFARI.
Awards & Honors
|August M. Watanabe Prize in Translational Research|
Indiana University School of Medicine
|Elaine Redding Brinster Prize in Science or Medicine|
Penn Institute for Regenerative Medicine at the University of Pennsylvania
|Kavli Prize in Neuroscience|
The Norwegian Academy of Science and Letters
The Lundbeck Foundation
|Victor McKusick Leadership Award|
American Society of Human Genetics
|National Academy of Inventors||01/2019|
|Norman J. Siegel Award|
American Pediatric Society
|National Order of the Cedar, Lebanon|
|Member of American Association of Arts and Sciences||01/2018|
|Canada Gairdner International Award||01/2017|
|Breakthrough Prize in Life Sciences||01/2017|
|Shaw Prize in Life Science and Medicine||01/2016|
|Jesse Stevenson Kovalenko Medal||01/2016|
|Vanderbilt Prize in Biomedical Science||01/2015|
McGovern Institute for Brain Research at MIT
|March of Dimes Prize in Developmental Biology|
March of Dimes
|Honorary Doctorate of Science|
|Dickson Prize in Medicine|
University of Pittsburg School of Medicine
|The Pearl Meister Greengard Prize|
The Rockefeller University
|Gruber Prize in Neuroscience||01/2011|
|Vilcek Prize for Biomedical Research||01/2009|
|International Rett Syndrome Foundation's Circle of Angels Research Award||01/2009|
|Marion Spencer Fay Award|
Drexel University College of Medicine
|Texas Women's Hall of Fame Award|
Texas Governor's Commission for Women
|Honorary Doctorate of Science|
Meharry Medical School
|Honorary Doctorate of Science|
|Robert J. and Claire Pasarow Foundation Award in Neuropsychiatry|
Los Angeles, CA
|Bristol-Myers Squibb Neuroscience Distinguished Achievement Award||01/2006|
National Academy of Sciences
|Marta Philipson Award in Pediatrics|
Philipson Foundation for Research
|Neuronal Plasticity Prize|
|Bernard Sachs Award|
Child Neurology Society
Institute of Medicine, National Academy of Sciences
NINDS Council, National Institutes of Health
The American Neurological Association
|Sidney Carter Award|
American Academy of Neurology
|E. Mead Johnson Award|
Society of Pediatric Research
|Kilby Award for Extraordinary Contributions to Society||01/1995|
Coffin SL, Durham MA, Nitschke L, Xhako E, Brown AM, Revelli J-P, Gonzalez EV, Lin T, Handler HP, Dai Y, Trostle AJ, Wan Y-W, Liu Z, Sillitoe RV, Orr HT, and Zoghbi HY. 2023. Disruption of the ATXN1-CIC complex reveals the role of additional nuclear ATXN1 interactors in spinocerebellar ataxia type 1. Neuron, in press.
Kim J, de Haro M, Al-Ramahi I, Garaicoechea L, Jeong H-H, Sonn J, Liu Z, Botas J, and Zoghbi HY. 2023. Evolutionarily conserved regulators of tau identify targets for new therapies. Neuron, in press
He L, Caudill MS, Jing J, Wang W, Sun Y, Tang J, Jiang X, Zoghbi HY. 2022. A weakened recurrent circuit in the hippocampus of Rett syndrome mice disrupts long-term memory representations. Neuron, May18;110(10):1689-1699. E6. PMID: 35290792.
This paper was the subject of a Neuron Editorial by Poll S and Fuhrmann M, May 18;110(10):1606-1608.
Achilly N, Wang W, Zoghbi HY. 2021. Presymptomatic training mitigates functional deficits in Rett syndrome mice. Nature.Apr;592(7855):596-600. PMCID: PMC8093094.
Shao, Y, Sztainberg Y, Wang Q, Bajikar SS, Trostle AJ, Wan Y-W, Jafar-Nejad P, Rigo F, Liu Z, Tang J, Zoghbi HY. 2021. Antisense oligonucleotide therapy in a humanized mouse model of MECP2 duplication syndrome. Sci Transl Med. Mar 3;13(583):eaaz7785. PMID: 33658357.