Huda Y. Zoghbi, M.D., Director

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.