John Marshall Professor of Medical Science

A major focus of our research is regulation of glutamate receptors that play key roles in neuronal communication. Failure to regulate these receptors can cause seizure disorders and neurodegeneration such as, Alzheimer's, Huntington's and Parkinson's disease. We have identified proteins that control the movement and localization of these receptors at synapses with the aim of designing drugs that prevent neuronal death in disease states.

We also study Angelman syndrome.  Our suggest that defective brain-derived neurotrophic factor (BDNF)/TrkB receptor signaling is responsible for observed cognitive impairment in humans.  At synapses, the activation of NMDA type glutamate receptors promotes the release of brain-derived neurotrophic factor (BDNF), which stimulates TrkB-PLCγ-CaMKII/CaMKIV-CREB and PI3K-Akt signaling pathways, required for the induction and maintenance of LTP.  We identified the synaptic scaffolding protein postsynaptic density-95 (PSD-95) as a novel drug target in the BDNF signaling pathway, and designed a novel prototypic cyclic peptide drug, CN2097, that reinstates BDNF signaling and long-term potentiation (LTP) in AS mice. 

I became interested in this line of research because I was interested in processes such as learning and memory. Receptors are key elements in the communication of neurons and by studying them we hope to understand at the molecular level how the brain functions.

Brown Affiliations

Research Areas

scholarly work

Cao C, Mengia SM., Migani P, Yu, CJ., Tiwari R., Parang K., Spaller MR, Goebel, DJ and Marshall J. Impairment of TrkB-PSD-95 signaling in Angelman Syndrome. Plos Biology 2013;11(2):e1001478. PMCID: PMC3570550

Wu, CH., Cao, C., Kim JH, Hsu CH, Wanebo HJ, Bowen WD, Xu J, Marshall J. Trojan-horse nanotube on-command intracellular drug delivery. Nano Lett. 2012 Nov 14; 12(11):5475-80. PMCID : PMC in process

Piserchio, A., Spaller, M., Marshall, J., and Mierke, D.F (2004) Targeting specific PDZ domains of PSD-95: Structural basis for enhanced affinity and enzymatic stability of a cyclic peptide Chemistry&Biology 11, 468-473.

Marshall, J., Blair, LAC., Singer JD (2011) BTB-Kelch proteins and ubiquitination of kainate receptors

Ad Exp Med Biol. 717:115-25.

Ren, Z., Riley, N., Needleman, L., Sanders JM, Swanson GT, Marshall J. (2003) Cell surface expression of GluR5 kainate receptors is regulated by an endoplasmic reticulum retention. J. Biol. Chem. 26;278(52):52700-9.

Marshall J, Dolan BM, Garcia EP, Sathe S, Tang X, Mao Z, Blair L.A.C. (2003) Calcium channel and NMDA receptor activity differentially regulate nuclear C/EBP levels to control neuronal survival. Neuron 39: 625-629.

research overview

Angelman syndrome (AS) is a severe neuro-genetic disorder resulting in severe intellectual and developmental disability with no available drug therapy.  AS is caused by loss of expression of the Ube3A ubiquitin ligase, resulting in dysregulation of downstream BDNF/TrkB signaling that interferes with the strengthening of synapses (long-term potentiation, LTP) and learning.  We identified the synaptic scaffolding protein postsynaptic density-95 (PSD-95) as a novel drug target in the BDNF signaling pathway, and designed a prototypic cyclic peptide drug, CN2097, that binds PSD-95 to reinstate BDNF signaling and long-term potentiation (LTP) in AS mice. 

research statement

Angelman syndrome (AS) is a severe neuro-genetic disorder resulting in severe intellectual and developmental disability with no available drug therapy.  A mouse model of AS, generated by targeted deletion of Ube3A5, shows impairment in long-lasting increases in synaptic strength (long term potentiation, LTP), the leading mechanism underlying learning. Deficits in LTP in the AS mouse have been attributed to reduced activity of α-calcium/calmodulin-dependent protein kinase II (CaMKII), as introducing a constitutively active form of CaMKII rescued LTP9.  Ube3A controls the levels of Arc (activity-regulated cytoskeletal-associated protein), whose expression is required for LTP consolidation12,13 and experience-dependent plasticity. 

Our studies in a mouse model of AS, suggest that defective brain-derived neurotrophic factor (BDNF)/TrkB receptor signaling is responsible for observed cognitive impairment in humans.  At synapses, the activation of NMDA type glutamate receptors promotes the release of brain-derived neurotrophic factor (BDNF), which stimulates TrkB-PLCγ-CaMKII/CaMKIV-CREB and PI3K-Akt signaling pathways, required for the induction and maintenance of LTP.  We discovered that BDNF-induced association of PSD-95 with the TrkB receptor is critical for intact BDNF signaling.  Arc, which is elevated in AS mice, interferes with the recruitment of PSD-95 to TrkB to inhibit BDNF signaling.  We identified the synaptic scaffolding protein postsynaptic density-95 (PSD-95) as a novel drug target in the BDNF signaling pathway, and designed a novel prototypic cyclic peptide drug, CN2097, that binds PSD-95 to displace Arc, to reinstate BDNF signaling and long-term potentiation (LTP) in AS mice.

funded research

1.  Treatment of Alzheimer’s Disease by Restoring Insulin/Akt Signaling, Brown Institute for Brain Science  1/01/2012-12/31/2014.  (Role: PI).

2.  Neuroprotection in TBI with a New Multifunctional Peptide-Based Therapeutic, Brown Institute for Brain Science  1/01/2012-12/31/2014.  (Role: Co-PI).


PENDING:

1.  R01NS086889-01  (Marshall) Role: Co-Principal Investigator

Neuroprotection in TBI with a New Multifunctional Peptide-Based Therapeutic

2.  Pharmaceutical company.  Marshall (PI)  Pharmacokinetic studies of CN2097.

In this proposal we focus on half-life studies, monitor the ability of CN2097 to cross the blood brain barrier, and perform a preliminary electrophysiology.  This pending proposal compliments and has little overlap with the submitted proposal

3.  R21MH104252-01  (Marshall) Role: Principal Investigator

A novel BDNF potentiator for Treating Cognitive Dysfunction in Angelman Syndrome

In this proposal we focus on the ability of CN2097 to rescue LTP impairment observed in the CA1 hippocampus of AS mice and examine the ability of CN2097 to mitigate neurobehavioral deficits.  The electrophysiology and behavioral studies in this R21 proposal do not overlap with those proposed.  However, if reviewers have concerns regarding overlap we will adjust the scope of budget appropriately.