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. 

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.

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.

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.

1995-1998 Upjohn Assistant Professor of Pharmacology
1993-1994 American Heart Fellowship
2000-2003 American Heart Established Investigator Award
2003-present Member, MBL Neuroscience Institute and Neuroimaging group
2003, 2004 Albert and Ellen Grass Faculty Award
2003-present NIH Study Section Reviewer

The Society for Neuroscience

1991-1993 Neurobiology course, Woods Hole.

1995-1996 Brown University, Physiology course (120 students)

1995-1998 Brown University, Director Medical School Pharmacology course (70 students)

1998-2000 Medical School Neuropharmacology lectures (70 students)

1998- present Brown University, Physiological Pharmacology- BIO 1260 (Pharmacology course, 35-80 students, I give about 25 (90 minute) lectures. A short list of the most common medically prescribed drugs will be discussed in terms of their fundamental modes of action and clinical importance e.g. the electrophysiology of the heart is discussed as a background to anti-arrhythmic drugs. A major focus of this course is signal transduction pathways and molecular biology of neurodegenerative diseases e.g. neurotrophic factors and the treatment of nerve disease (Motor neuron, Parkinson's), pathogenesis of Alzheimer's disease, Stem cell transplantation. Students are introduced to increasingly important aspects of treatments such as recombinant DNA techniques and gene therapy.

 

Bio 2260-(Pharmacology course, 5-10 graduate students, I give about 25 (90 minute) lectures. A short list of the most common medically prescribed drugs will be discussed in terms of their fundamental modes of action and clinical importance.  A major focus of this course is signal transduction pathways and molecular biology of neurodegenerative diseases e.g. neurotrophic factors and the treatment of nerve disease (Motor neuron, Parkinson's), pathogenesis of Alzheimer's disease, Stem cell transplantation. Students are introduced to increasingly important aspects of treatments such as recombinant DNA techniques and gene therapy.