Huda Y. Zoghbi, M.D., Director

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.