When:
Thursday, September 21, 2023
2:00 PM - 3:00 PM CT
Where: Ward Building, 5-230, 303 E. Chicago Avenue, Chicago, IL 60611 map it
Audience: Faculty/Staff - Student - Post Docs/Docs - Graduate Students
Contact:
Wesley Gryziak
Group: Center for Autism and Neurodevelopment
Category: Lectures & Meetings
"Upregulation of SYNGAP1 in models of human diseases by redirecting alternative splicing"
The Ras GTPase-activating protein SYNGAP1 plays a central role in synaptic plasticity, and de novo SYNGAP1 mutations are among the most frequent causes of autism and intellectual disability. How SYNGAP1 is regulated during development and how to treat SYNGAP1-associated haploinsufficiency remain challenging questions. Here, we characterize an alternative 3′ splice site (A3SS) of SYNGAP1 that induces nonsense-mediated mRNA decay (A3SS-NMD) in mouse and human neural development. We demonstrate that PTBP1/2 directly bind to and promote SYNGAP1 A3SS inclusion. Genetic deletion of the Syngap1 A3SS in mice upregulates Syngap1 protein and alleviates the long-term potentiation and membrane excitability deficits caused by a Syngap1 knockout allele. We further report a splice-switching oligonucleotide (SSO) that converts SYNGAP1 unproductive isoform to the functional form in human iPSC-derived neurons. This study describes the regulation and function of SYNGAP1 A3SS-NMD, the genetic rescue of heterozygous Syngap1 knockout mice, and the development of an SSO to potentially alleviate SYNGAP1-associated haploinsufficiency.
Thursday September 21, 2023
CAN Seminar Series
2:00 PM - 3:00 PM
Location: Ward 5-230
Xiaochang Zhang, PhD
Assistant Professor, Department of Human Genetics
Member, the Neuroscience Institute
University of Chicago