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Multimodal Analysis of STRADA Function in Brain Development

Authors :
Louis T. Dang
Katarzyna M. Glanowska
Philip H. Iffland II
Allan E. Barnes
Marianna Baybis
Yu Liu
Gustavo Patino
Shivanshi Vaid
Alexandra M. Streicher
Whitney E. Parker
Seonhee Kim
Uk Yeol Moon
Frederick E. Henry
Geoffrey G. Murphy
Michael Sutton
Jack M. Parent
Peter B. Crino
Source :
Frontiers in Cellular Neuroscience, Vol 14 (2020)
Publication Year :
2020
Publisher :
Frontiers Media S.A., 2020.

Abstract

mTORopathies are a heterogeneous group of neurological disorders characterized by malformations of cortical development (MCD), enhanced cellular mechanistic target of rapamycin (mTOR) signaling, and epilepsy that results from mutations in mTOR pathway regulatory genes. Homozygous mutations (del exon 9–13) in the pseudokinase STE20-related kinase adaptor alpha (STRAD-α; STRADA), an mTOR modulator, are associated with Pretzel Syndrome (PS), a neurodevelopmental disorder within the Old Order Mennonite Community characterized by megalencephaly, intellectual disability, and intractable epilepsy. To study the cellular mechanisms of STRADA loss, we generated CRISPR-edited Strada mouse N2a cells, a germline mouse Strada knockout (KO−/−) strain, and induced pluripotent stem cell (iPSC)-derived neurons from PS individuals harboring the STRADA founder mutation. Strada KO in vitro leads to enhanced mTOR signaling and iPSC-derived neurons from PS individuals exhibit enhanced cell size and mTOR signaling activation, as well as subtle alterations in electrical firing properties e.g., increased input resistance, a more depolarized resting membrane potential, and decreased threshold for action potential (AP) generation. Strada−/− mice exhibit high rates of perinatal mortality and out of more than 100 litters yielding both WT and heterozygous pups, only eight Strada−/− animals survived past P5. Strada−/− mice are hypotonic and tremulous. Histopathological examination (n = 5 mice) revealed normal gross brain organization and lamination but all had ventriculomegaly. Ectopic neurons were seen in all five Strada−/− brains within the subcortical white matter mirroring what is observed in human PS brain tissue. These distinct experimental platforms demonstrate that STRADA modulates mTOR signaling and is a key regulator of cell size, neuronal excitability, and cortical lamination.

Details

Language :
English
ISSN :
16625102 and 53413016
Volume :
14
Database :
Directory of Open Access Journals
Journal :
Frontiers in Cellular Neuroscience
Publication Type :
Academic Journal
Accession number :
edsdoj.53413016f1094d83a21051ee639df779
Document Type :
article
Full Text :
https://doi.org/10.3389/fncel.2020.00122