STRADalpha deficiency results in aberrant mTORC1 signaling during corticogenesis in humans and mice.
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 alpha (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. STRADalpha 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 STRADalpha expression. STRADalpha-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 STRADalpha 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 STRADalpha deficiency contributes to hyperactivation of mTORC1 signaling and disruption of neuronal lamination during corticogenesis, and thereby the neurological features associated with PMSE.
Orlova
Ksenia A
KA
Department of Neurology, Penn Epilepsy Center, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104, USA.
Parker
Whitney E
WE
Heuer
Gregory G
GG
Tsai
Victoria
V
Yoon
Jason
J
Baybis
Marianna
M
Fenning
Robert S
RS
Strauss
Kevin
K
Crino
Peter B
PB
D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001921:Brain / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008954:Models, Biological; D046912:Multiprotein Complexes; D009474:Neurons / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011506:Proteins; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000378:metabolism*
D033942:Adaptor Proteins, Vesicular Transport; D046912:Multiprotein Complexes; D011506:Proteins; C518004:STRAD protein, mouse; C476400:STRADA protein, human; D014157:Transcription Factors; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; C491654:Stk11 protein, mouse; D058570:TOR Serine-Threonine Kinases; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases