mTOR: A pathogenic signaling pathway in developmental brain malformations

Trends Mol Med. 2011 Dec;17(12):734-42. doi: 10.1016/j.molmed.2011.07.008. Epub 2011 Sep 2.

Abstract

The mTOR signaling network functions as a pivotal regulatory cascade during the development of the cerebral cortex. Aberrant hyperactivation of mTOR as a consequence of loss-of-function gene mutations encoding mTOR inhibitor proteins such as TSC1, TSC2, PTEN and STRADα has been recently linked to developmental cortical malformations associated with epilepsy and neurobehavioral disabilities. Investigation of mTOR signaling in these disorders provides for the first time exciting future avenues for assessment of biomarkers, patient stratification and prognostic measures as well as the opportunity for targeted therapy to regulate mTOR activity across all age groups. As we learn more about mTOR and its activity in the developing brain, many challenges will arise that must be overcome before widespread clinical therapeutics can be implemented.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Adaptor Proteins, Vesicular Transport / genetics
  • Adaptor Proteins, Vesicular Transport / metabolism
  • Animals
  • Autistic Disorder / drug therapy
  • Autistic Disorder / metabolism
  • Autistic Disorder / pathology
  • Autistic Disorder / physiopathology*
  • Biomarkers / metabolism
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / metabolism
  • Cerebral Cortex / pathology*
  • Cerebral Cortex / physiopathology
  • Epilepsy / drug therapy
  • Epilepsy / metabolism
  • Epilepsy / pathology
  • Epilepsy / physiopathology*
  • Humans
  • Malformations of Cortical Development / drug therapy
  • Malformations of Cortical Development / metabolism
  • Malformations of Cortical Development / pathology*
  • Malformations of Cortical Development / physiopathology
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Molecular Targeted Therapy / methods*
  • Multiprotein Complexes
  • Mutation
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / metabolism
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / therapeutic use
  • Proteins / antagonists & inhibitors
  • Proteins / genetics
  • Proteins / metabolism
  • Signal Transduction / genetics*
  • Sirolimus / administration & dosage*
  • Sirolimus / therapeutic use
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism*
  • Tuberous Sclerosis Complex 1 Protein
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism

Substances

  • Adaptor Proteins, Vesicular Transport
  • Biomarkers
  • Multiprotein Complexes
  • Protein Kinase Inhibitors
  • Proteins
  • STRAD protein, human
  • TSC1 protein, human
  • TSC2 protein, human
  • Tsc1 protein, mouse
  • Tsc2 protein, mouse
  • Tuberous Sclerosis Complex 1 Protein
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Sirolimus