NDLI: STRADα deficiency results in aberrant mTORC1 signaling during corticogenesis in humans and mice

Content Provider	PubMed Central
Author	Orlova, Ksenia A. Parker, Whitney E. Heuer, Gregory G. Tsai, Victoria Yoon, Jason Baybis, Marianna Fenning, Robert S. Strauss, Kevin Crino, Peter B.
Abstract	Polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome (PMSE) is a rare human autosomal-recessive disorder characterized by abnormal brain development, cognitive disability, and intractable epilepsy. It is caused by homozygous deletions of STE20-related kinase adaptor α (STRADA). The underlying pathogenic mechanisms of PMSE and the role of STRADA in cortical development remain unknown. Here, we found that a human PMSE brain exhibits cytomegaly, neuronal heterotopia, and aberrant activation of mammalian target of rapamycin complex 1 (mTORC1) signaling. STRADα normally binds and exports the protein kinase LKB1 out of the nucleus, leading to suppression of the mTORC1 pathway. We found that neurons in human PMSE cortex exhibited abnormal nuclear localization of LKB1. To investigate this further, we modeled PMSE in mouse neural progenitor cells (mNPCs) in vitro and in developing mouse cortex in vivo by knocking down STRADα expression. STRADα-deficient mNPCs were cytomegalic and showed aberrant rapamycin-dependent activation of mTORC1 in association with abnormal nuclear localization of LKB1. Consistent with the observations in human PMSE brain, knockdown of STRADα in vivo resulted in cortical malformation, enhanced mTORC1 activation, and abnormal nuclear localization of LKB1. Thus, we suggest that the aberrant nuclear accumulation of LKB1 caused by STRADα deficiency contributes to hyperactivation of mTORC1 signaling and disruption of neuronal lamination during corticogenesis, and thereby the neurological features associated with PMSE.
Related Links	http://dx.doi.org/10.1172/jci41592
Ending Page	1602
Page Count	12
Starting Page	1591
File Format	PDF
ISSN	00219738
e-ISSN	15588238
Journal	The Journal of Clinical Investigation
Issue Number	5
Volume Number	120
Language	English
Publisher	American Society for Clinical Investigation
Publisher Date	2010-05-03
Access Restriction	Open
Rights Holder	American Society for Clinical Investigation
Subject Keyword	Medicine(all) Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Medicine

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1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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