My laboratory uses biochemical approaches, guided by human genetics, to probe the fundamental mechanisms underlying neurodegenerative diseases and neurodevelopmental disorders. We use precise genetic disease cells/mouse models and human patient cells. Two conditions we are currently focused on are Huntington’s disease and CDKL5 deficiency disorder.

Our research into the structural, biochemical, and functional properties of the full-length huntingtin protein continues to aim to understand Huntington’s disease (HD) at its root cause. Given the discovery that loss-of-function mutations in HTT underlie LOMARS, a severe recessive neurodevelopmental condition, we recently showed that mutations in LOMARS subjects dramatically reduce but do not eliminate huntingtin via two mechanisms: altered splicing and altered huntingtin stability. These findings have had profound implications for the testing of huntingtin-lowering treatments, one of the main therapeutic avenues currently in clinical trials for Huntington’s disease, with two valuable novel models: LOMARS patient-derived induced pluripotent stem differentiated into neuronal cells and HD mouse lines harboring a huntingtin-destabilizing missense mutation.

We also expanded our work to characterize newly discovered neurodevelopmental disorder genes—for example, CDKL5, to understand the mechanism of CDKL5 deficiency disorder (CDD) and developed target mass spectrometry assays that distinguish isoforms, activity (critical autophosphorylation at Tyr171) and substrates for this kinase.

Finally, with our expertise and resources, we have expanded our research to investigate several strong candidate genes as a HD genetic modifier suggested from the genome-wide association study with HD patients. In both neurodegenerative and neurodevelopmental disorders, our application of biochemistry guided by human genetics will continue to elucidate the fundamental causes of disease while suggesting routes for mechanism-based treatments.