Current projects
Many chromatin modifiers and transcription factors have been associated with epilepsy and autism spectrum disorder (ASD). One of these chromatin modifiers is the gene Absent, small, or homeotic-like (ASH1L). Mutations in the ASH1L gene results in epilepsy and ASD. We characterized a mouse model of ASH1L with respect to its epilepsy phenotype and electrophysiology. Recently, we identified a sex difference within our patients, with epilepsy predominantly in females and ASD in males. These findings have further advanced our understanding of the role of ASH1L and potential therapy from a sex-dimorphic perspective.
SLC13A5 citrate transporter disorder is a rare genetic disorder. The disease phenotype is epilepsy that starts in the neonatal period and can be difficult to control. Over time, other phenotypes become apparent, including motor delays and impaired speech. The normal function of SLC13A5 may be related to loss-of-function phenotypes in patients. How mutations in SLC13A5 can result in disease is unknown. Work in animal models will guide the development of gene therapy for this disorder. Beyond creating & characterizing animal models and determining the genetic mechanism of infantile epileptic encephalopathy, we have also conducted clinical research on the disorder This work, in collaboration with the family group the TESS Research Foundation, is funded by a Rare as One Project by the Chan Zuckerberg Initiative.
Epilepsy can arise from developmental defects, and later in life, circuit changes resulting from injury can cause even more seizures. In both processes, the cytoskeleton, the cell's system for growing and maintaining the specialized shape of neurons, can play a crucial role.
We previously studied doublecortin (DCX), which is essential for regulating molecular motors in the microtubule cytoskeleton and is the causative gene for lissencephaly (smooth brain). In the absence of DCX, the binding of the adaptor protein JIP3 to the dynein motor complex increases, thereby enhancing dynein-mediated retrograde transport. Through a collaboration with the Wolverine Foundation, we are currently investigating how JIP3 causes a newly defined rare disease that is associated with developmental delays, seizures, hypotonia, and spasticity.
In addition, we found that a protein related to DCX, doublecortin-like kinase (DCLK1), is upregulated in cases of human focal epilepsy. Our ongoing work characterizing the role of DCLK1 in epilepsy shows that the formation of abnormal branches in mossy fibers, or “mossy fiber sprouting,” is greatly increased over baseline in mice with targeted deletions of DCLK1. We have further demonstrated that deletion of DCLK1 leads to increased epileptiform activity and abnormally elevated activity in structures downstream of the dentate gyrus.