PMID- 37149062
OWN - NLM
STAT- MEDLINE
DCOM- 20230607
LR  - 20230609
IS  - 1095-953X (Electronic)
IS  - 0969-9961 (Linking)
VI  - 182
DP  - 2023 Jun 15
TI  - mTOR pathway: Insights into an established pathway for brain mosaicism in 
      epilepsy.
PG  - 106144
LID - S0969-9961(23)00158-4 [pii]
LID - 10.1016/j.nbd.2023.106144 [doi]
AB  - The mechanistic target of rapamycin (mTOR) signaling pathway is an essential 
      regulator of numerous cellular activities such as metabolism, growth, 
      proliferation, and survival. The mTOR cascade recently emerged as a critical 
      player in the pathogenesis of focal epilepsies and cortical malformations. The 
      'mTORopathies' comprise a spectrum of cortical malformations that range from 
      whole brain (megalencephaly) and hemispheric (hemimegalencephaly) abnormalities 
      to focal abnormalities, such as focal cortical dysplasia type II (FCDII), which 
      manifest with drug-resistant epilepsies. The spectrum of cortical dysplasia 
      results from somatic brain mutations in the mTOR pathway activators AKT3, MTOR, 
      PIK3CA, and RHEB and from germline and somatic mutations in mTOR pathway 
      repressors, DEPDC5, NPRL2, NPRL3, TSC1 and TSC2. The mTORopathies are 
      characterized by excessive mTOR pathway activation, leading to a broad range of 
      structural and functional impairments. Here, we provide a comprehensive 
      literature review of somatic mTOR-activating mutations linked to epilepsy and 
      cortical malformations in 292 patients and discuss the perspectives of targeted 
      therapeutics for personalized medicine.
CI  - Copyright (c) 2023. Published by Elsevier Inc.
FAU - Gerasimenko, Anna
AU  - Gerasimenko A
AD  - Sorbonne Universite, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, 
      CNRS, Hopital de la Pitie Salpetriere, 75013 Paris, France; APHP Sorbonne 
      Universite, GH Pitie Salpetriere et Trousseau, Departement de Genetique, Centre 
      de reference "deficiences intellectuelles de causes rares", Paris, France.
FAU - Baldassari, Sara
AU  - Baldassari S
AD  - Sorbonne Universite, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, 
      CNRS, Hopital de la Pitie Salpetriere, 75013 Paris, France.
FAU - Baulac, Stephanie
AU  - Baulac S
AD  - Sorbonne Universite, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, 
      CNRS, Hopital de la Pitie Salpetriere, 75013 Paris, France. Electronic address: 
      stephanie.baulac@icm-institute.org.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Review
DEP - 20230504
PL  - United States
TA  - Neurobiol Dis
JT  - Neurobiology of disease
JID - 9500169
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - 0 (NPRL3 protein, human)
RN  - 0 (GTPase-Activating Proteins)
SB  - IM
MH  - Humans
MH  - Mosaicism
MH  - Mutation/genetics
MH  - Brain/metabolism
MH  - *Epilepsy/genetics/metabolism
MH  - TOR Serine-Threonine Kinases/genetics/metabolism
MH  - *Malformations of Cortical Development/metabolism
MH  - GTPase-Activating Proteins/genetics
OTO - NOTNLM
OT  - Brain mosaicism
OT  - Cortical development
OT  - Cortical malformation
OT  - Epilepsy
OT  - FCDII
OT  - Hemimegalencephaly
OT  - Megalencephaly
OT  - Somatic mutations
OT  - mTOR signaling
COIS- Declaration of Competing Interest None.
EDAT- 2023/05/07 00:42
MHDA- 2023/06/07 06:42
CRDT- 2023/05/06 19:28
PHST- 2023/03/12 00:00 [received]
PHST- 2023/05/02 00:00 [revised]
PHST- 2023/05/03 00:00 [accepted]
PHST- 2023/06/07 06:42 [medline]
PHST- 2023/05/07 00:42 [pubmed]
PHST- 2023/05/06 19:28 [entrez]
AID - S0969-9961(23)00158-4 [pii]
AID - 10.1016/j.nbd.2023.106144 [doi]
PST - ppublish
SO  - Neurobiol Dis. 2023 Jun 15;182:106144. doi: 10.1016/j.nbd.2023.106144. Epub 2023 
      May 4.