Johns Hopkins School of Medicine

Regulation and Function of the Neuronal Membrane Proteasome from Development to Disease

Dr. Margolis has a broad background and expertise in using biochemical, proteomic, molecular cellular, mouse genetic, and behavior approaches to dissect protein homeostasis signaling mechanisms in neuronal biology. Over the years Dr. Margolis and his team has focused the laboratories efforts toward the ubiquitin proteasome pathways and actin cytoskeleton control of early developmental excitatory synapse formation in healthy and diseased brain states. They have spent considerable effort investigating the functions of an ubiquitin ligase, UBE3A in neural development and its role in the human cognitive disorder Angelman syndrome. Specifically, they have been identifying the substrates of UBE3A that are targeted for proteasome-mediated degradation. UBE3A itself and at least one of these substrates is relevant to Alzheimer’s disease. They have since aimed part of our efforts to advancing an understanding of protein degradation mechanisms relevant to Alzheimer’s disease (AD) etiology. 

In the course of their studies, Dr. Margolis and his team made an unexpected discovery which was built logically on the laboratories long standing interests. In short, they discovered a novel neuronal specific membrane associated proteasome complex that through extracellular proteasome-derived peptides modulates neuronal signaling. This system is contributes to activity dependent neuronal signaling and is disrupted in disease. The robustness, uniqueness, and reproducibility have kept them moving forward in order to generate significant future advances in tools and information to comprehend the role of this signaling in the nervous system both in health and disease.  In the long term, Dr. Margolis envisions the lab following these pathways to address the following questions:

• What are the substrates of this proteasome complex and the sequences of the signaling peptides? 
• How do these NMP derived peptides mediate their signaling capacity and specificity?
• What is the full make-up of the neuronal membrane proteasome (NMP) complex and how is it regulated?
• What is the importance of this pathway to neuronal physiology and animal behavior in health and disease?

They hope to leverage their findings in order to better define this emerging field and provide the tools and information important for their research and the field of cellular and molecular neuroscience as a whole.