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Seth S. Margolis, Ph.D.

Photo of Dr. Seth S. Margolis, Ph.D.

Associate Professor of Biological Chemistry

Research Interests: Molecular mechanisms of synapse formation and protein homeostasis in brain function; development and disease


Dr. Seth Shatkin Margolis is an Associate Professor in the Department of Biological Chemistry with a Secondary appointment in the Sol Snyder Department of Neuroscience at the Johns Hopkins University School of Medicine. Dr. Margolis and his research team are focused on the molecular mechanisms of synapse formation and neuronal function in development and disease. They have a specific interest in the protein homeostasis machinery (protein translation and protein degradation) that control these processes.

Through new discoveries they now have a significant effort aimed at investigating the role of a novel neuronal specific proteasome complex and a unique class of extracellular signaling peptides that it produces.

Dr. Margolis received his undergraduate degree in biochemistry from the University of Rochester and earned his Ph.D. from Duke University. He completed postdoctoral training in neurobiology at Harvard Medical School. Dr. Margolis joined the Johns Hopkins faculty in 2011.

His work has been recognized with several awards, including The Edward R. and Anne G. Lefler Postdoctoral Fellowship from 2009 to 2011, NIH funding and funding from several foundations. more


  • Associate Professor of Biological Chemistry
  • Associate Professor of Neuroscience



  • B.S., University of Rochester (New York) (1997)
  • Ph.D., Duke University (North Carolina) (2005)

Additional Training

Postdoctoral Training, Harvard Medical School, Boston, MA, 2011, Neurobiology

Research & Publications

Research Summary

Dr. Margolis' laboratory is focused on studying the molecular pathways that regulate excitatory synapse formation and investigating their relevance to the pathophysiology of cognitive disorders. Combining molecular biology, genetics, biochemistry and cell biological approaches in the mouse model system, they have discovered a molecular link between a major regulator of excitatory synapse development, EphB2, and Ube3A, an E3 ubiquitin ligase that is mutated in the human cognitive disorder Angelman Syndrome (AS) and duplicated in some forms of Autism Spectrum Disorders (ASDs). Their immediate goal is to further dissect and understand this EphB2/Ube3A interaction during non-pathological brain development. Their long-term goal is to address how, when these molecular pathways go awry, human cognitive disorders such as AS and ASDs develop.


Currently projects in Dr. Margolis' lab include studies of:

1) Ephexin5: Ephexin5 is a guanine nucleotide-exchange factor (GEF) that activates the small G-protein RhoA, a regulator of the actin cytoskeleton. Genetic loss- and gain-of-function studies indicate that Ephexin5 acts to restrict spine growth and synapse development in the developing brain. Upon induction of EphrinB/EphB ligand-receptor signaling, Ephexin5 is rapidly phosphorylated in an EphB-dependent manner and targeted for proteasome-dependent degradation. These findings suggest that Ephexin5 functions as a barrier to excitatory synapse development until its degradation is triggered by EphrinB binding to EphBs. Interestingly, the degradation of Ephexin5 is mediated by Ube3A, a ubiquitin ligase whose expression level is altered in the human cognitive disorder Angelman Syndrome (AS) and in some forms of autism. This suggests that aberrant EphB/Ephexin5 signaling during synaptic development may contribute to the abnormal cognitive function observed in AS and autism.

2) New regulators of synapse formation: The goal of this study will be to identify additional components of the genetic program that restrict synapse numbers using previously developed immunocytochemistry-based assay for neuronal synaptic connections in vitro. Specific targets will be corroborated using electrophysiological and in vivo morphological measurements. Dr. Margolis and his team are particularly interested in genes whose products function to restrict synapse formation early in development and are suggested to be defective or inappropriately activated in cognitive disorders.

Lab Website: Margolis Lab

Selected Publications

Schaffer TB, Smith JE, Cook EK, Phan T, Margolis SS. PKCε Inhibits Neuronal Dendritic Spine Development through Dual Phosphorylation of Ephexin5. Cell Rep. (2018) Nov 27;25(9):2470-2483.e8. doi: 10.1016/j.celrep.2018.11.005.

Ramachandran KV, Fu JM, Schaffer TB, Na CH, Delannoy M, Margolis SS. Activity-Dependent Degradation of the Nascentome by the Neuronal Membrane Proteasome. Mol Cell. (2018) Jul 5;71(1):169-177.e6. doi: 10.1016/j.molcel.2018.06.013.

Sell GL, Schaffer TB, Margolis SS. Reducing expression of synapse-restricting protein Ephexin5 ameliorates Alzheimer's-like impairment in mice. J Clin Invest. (2017) May 1;127(5):1646-1650. doi: 10.1172/JCI85504.

Ramachandran KV, Margolis SS. A mammalian nervous-system-specific plasma membrane proteasome complex that modulates neuronal function. Nat Struct Mol Biol. (2017) Apr;24(4):419-430. doi: 10.1038/nsmb.3389.

Academic Affiliations & Courses

Graduate Program Affiliation

Graduate Program in Biochemistry, Cell, and Molecular Biology

Graduate Program in Neuroscience

Graduate Program in Biological Chemistry

Activities & Honors

Professional Activities

  • Co-Director and Admissions Committee, Basic Science Institute Summer Internship Program (BSI-SIP), The Johns Hopkins University School of Medicine
  • Advisory Board, XDBio Graduate Program, The Johns Hopkins University School of Medicine
  • Co-Director,, BCMB Graduate Program Retreat,, The Johns Hopkins University School of Medicine, 2013
  • Representative for Department of Biological Chemistry, Faculty Senate, The Johns Hopkins University School of Medicine
  • Member,, BCMB Graduate Admissions Committee, 2019

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