한빛사 논문
Jeffrey S. Burgdorf1,2,7, Sehyoun Yoon3,7, Marc Dos Santos3, Catherine R. Lammert3, Joseph R. Moskal1,2 and Peter Penzes3,4,5,6
1Falk Center for Molecular Therapeutics, Department of Biomedical Engineering, McCormick School of Engineering, Northwestern University, Evanston, IL 60201, USA.
2Gate neurosciences, Inc., Carmel, IN 46032, USA.
3Department of Neuroscience, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
4Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
5Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
6Northwestern University, Center for Autism and Neurodevelopment, Chicago, IL 60611, USA.
7These authors contributed equally: Jeffrey S. Burgdorf, Sehyoun Yoon
Corresponding author : Correspondence to Peter Penzes.
Abstract
We developed an IGFBP2-mimetic peptide fragment, JB2, and showed that it promotes basal synaptic structural and functional plasticity in cultured neurons and mice. We demonstrate that JB2 directly binds to dendrites and synapses, and its biological activity involves NMDA receptor activation, gene transcription and translation, and IGF2 receptors. It is not IGF1 receptor-dependent. In neurons, JB2 induced extensive remodeling of the membrane phosphoproteome. Synapse and cytoskeletal regulation, autism spectrum disorder (ASD) risk factors, and a Shank3-associated protein network were significantly enriched among phosphorylated and dephosphorylated proteins. Haploinsufficiency of the SHANK3 gene on chromosome 22q13.3 often causes Phelan-McDermid Syndrome (PMS), a genetically defined form of autism with profound deficits in motor behavior, sensory processing, language, and cognitive function. We identified multiple disease-relevant phenotypes in a Shank3 heterozygous mouse and showed that JB2 rescued deficits in synaptic function and plasticity, learning and memory, ultrasonic vocalizations, and motor function; it also normalized neuronal excitability and seizure susceptibility. Notably, JB2 rescued deficits in the auditory evoked response latency, alpha peak frequency, and steady-state electroencephalography response, measures with direct translational value to human subjects. These data demonstrate that JB2 is a potent modulator of neuroplasticity with therapeutic potential for the treatment of PMS and ASD.
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