Current Research

Characterizing the function of Norrin and the molecular mechanisms underlying Norrie Disease

Norrie Disease is a rare neurodevelopmental disorder that is characterized by blindness at birth, progressive hearing loss, and cognitive impairment such as mental retardation, seizures, and behavioral disturbances. Mutations to the NDP gene, which encodes the protein Norrin, are responsible for the early onset of Norrie Disease in patients. To read more about Norrie Disease, visit norriedisease.org.

Outside of the extensively characterized roles of Norrin in the retina, where Norrin is critical for vascular development, the contribution of Norrin to brain function was not well understood. Recently, however, we uncovered a subpopulation of astrocytes in the cortex that secrete Norrin which in turn regulates neuronal function (Miller et al., 2019). Currently, we are working to understand the molecular role that Norrin plays in neuronal-astrocytic communication, at neuronal synapses, and how these findings could translate to neurodegeneration and neurodevelopmental disorders like Norrie Disease.

Investigating nuclear pore complex compositional changes throughout the OPC lineage

The nuclear pore complex (NPC) is a massive structure of proteins that functions primarily as the gate between the nucleus and the cytoplasm (though various components play a role in many other cellular processes). While the general structure of the NPC is conserved across cell types, small differences in the composition, number, and spacing of a cell’s NPCs could have significant implications for the function of that cell. We are currently investigating differences in the composition and structure of NPCs as oligodendrocyte precursor cells (OPCs) differentiate and mature into oligodendrocytes.

Assessing the role of Tau aggregation on nuclear pore complex structure and function

Aggregation of Tau protein into “Tau tangles” is one of the main putative drivers of Alzheimer’s Disease (AD). Recently, we have described a mechanism by which Nup98, a component of the NPC, is sequestered within Tau aggregates (Eftekharzadeh et al., 2018). Additionally, we observed that Nup98 may contribute to the initial fibrillization of Tau. We are now working to investigate whether Tau aggregation contributes to any other changes in the NPC.

Determining the molecular events that initiate ALS pathogenesis

Amyotrophic Laterals Sclerosis (ALS), otherwise known as Lou Gehrig’s Disease or Motor Neuron Disease, is a progressive and fatal neurodegenerative disease. ALS leads to the death of motor neurons, which are the cells that allow for control of one’s muscles. While a small percentage of ALS cases are caused by inherited mutations in a variety of genes, the vast majority (>85%) arise from unknown causes. These “sporadic” cases warrant our current investigation into the molecular events that drive the onset of ALS.

Our current work is focused on understanding the initiators of NPC dysfunction, as well as how these alterations contribute to other known hallmarks of ALS.