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Plasticity and mTOR: towards restoration of impaired synaptic plasticity in mTOR-related neurogenetic disorders.

Gipson TT, Johnston MV - Neural Plast. (2012)

Bottom Line: This paper revealed significant similarities among the conditions.Not only do they share features of impaired synaptic plasticity and dysregulation of mTOR, but they also share clinical features--autism, intellectual disability, cutaneous lesions, and tumors.Although scientific advances towards discovery of effective treatment in some disorders have outpaced others, progress in understanding the signaling pathways that connect the entire group indicates that the lesser known disorders will become treatable as well.

View Article: PubMed Central - PubMed

Affiliation: Tuberous Sclerosis Center, Hugo Moser Research Institute, Kennedy Krieger Institute, Baltimore, MD 21205, USA. gipson@kennedykrieger.org

ABSTRACT

Objective: To review the recent literature on the clinical features, genetic mutations, neurobiology associated with dysregulation of mTOR (mammalian target of rapamycin), and clinical trials for tuberous sclerosis complex (TSC), neurofibromatosis-1 (NF1) and fragile X syndrome (FXS), and phosphatase and tensin homolog hamartoma syndromes (PTHS), which are neurogenetic disorders associated with abnormalities in synaptic plasticity and mTOR signaling.

Methods: Pubmed and Clinicaltrials.gov were searched using specific search strategies.

Results/conclusions: Although traditionally thought of as irreversible disorders, significant scientific progress has been made in both humans and preclinical models to understand how pathologic features of these neurogenetic disorders can be reduced or reversed. This paper revealed significant similarities among the conditions. Not only do they share features of impaired synaptic plasticity and dysregulation of mTOR, but they also share clinical features--autism, intellectual disability, cutaneous lesions, and tumors. Although scientific advances towards discovery of effective treatment in some disorders have outpaced others, progress in understanding the signaling pathways that connect the entire group indicates that the lesser known disorders will become treatable as well.

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Related in: MedlinePlus

Pathways associated with neurogenetic conditions linked by mTOR and impaired synaptic plasticity. AKT-v—akt murine thymoma viral oncogene homolog 1; AMPK—adenosine monophosphate kinase; ATP—adenosine triphosphate; EIF4E/4EBP1—eukaryotic translation initiation factor 4E-binding protein 1; ERK—extracellular signal-related kinase; FKB12-FK506—binding protein family; FMRP—fragile X mental retardation protein; GBL/LST8—(mTOR-associated protein, LST8 homolog); GDP—guanosine diphosphate; GTP—guanosine triphosphate; GDP—guanosine diphosphate; HIF1α—hypoxia inducible factor 1, alpha subunit IGF—insulin-like growth factor; IGFR—insulin-like growth factor receptor; IRS—insulin receptor substrate; LKB1—serine threonine kinase 11; mTORC1—mammalian target of rapamycin complex 1; mTORC2—mammalian target of rapamycin complex 2; MEK—dual specificity mitogen-activated protein kinase 1; NF-1—neurofibromatosis 1; P/+ Thr308—phosphorylation of threonine, position 308; P/+ Ser473—phosphorylation of serine, position 473; PDK1—pyruvate dehydrogenase kinase, isozyme 1; PDK 2—pyruvate dehydrogenase kinase, isozyme 2; PI3K—phosphoinositide-3-kinase; PIKE—phosphoinositide 3-kinase enhancer; PIP1—p21-activated protein kinase-interacting protein 1 (PAK1 interacting protein 1); PIP2—phosphatidylinositol 4,5-biphosphate; PIP3—phosphatidylinositol (3,4,5)-triphosphate; PTEN—phosphatase and tensin homolog; RAS—Ras p21 protein activator 1 or RAS GTPase activating protein; REDD1—regulated in development and DNA damage responses; RHEB—Ras homologue expressed in brain; RTK—receptor tyrosine kinase; S6K—ribosomal protein S6 kinase; TSC—tuberous sclerosis complex; VEGF—vascular endothelial growth factor; VHL—von Hippel Lindau.
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Related In: Results  -  Collection


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fig1: Pathways associated with neurogenetic conditions linked by mTOR and impaired synaptic plasticity. AKT-v—akt murine thymoma viral oncogene homolog 1; AMPK—adenosine monophosphate kinase; ATP—adenosine triphosphate; EIF4E/4EBP1—eukaryotic translation initiation factor 4E-binding protein 1; ERK—extracellular signal-related kinase; FKB12-FK506—binding protein family; FMRP—fragile X mental retardation protein; GBL/LST8—(mTOR-associated protein, LST8 homolog); GDP—guanosine diphosphate; GTP—guanosine triphosphate; GDP—guanosine diphosphate; HIF1α—hypoxia inducible factor 1, alpha subunit IGF—insulin-like growth factor; IGFR—insulin-like growth factor receptor; IRS—insulin receptor substrate; LKB1—serine threonine kinase 11; mTORC1—mammalian target of rapamycin complex 1; mTORC2—mammalian target of rapamycin complex 2; MEK—dual specificity mitogen-activated protein kinase 1; NF-1—neurofibromatosis 1; P/+ Thr308—phosphorylation of threonine, position 308; P/+ Ser473—phosphorylation of serine, position 473; PDK1—pyruvate dehydrogenase kinase, isozyme 1; PDK 2—pyruvate dehydrogenase kinase, isozyme 2; PI3K—phosphoinositide-3-kinase; PIKE—phosphoinositide 3-kinase enhancer; PIP1—p21-activated protein kinase-interacting protein 1 (PAK1 interacting protein 1); PIP2—phosphatidylinositol 4,5-biphosphate; PIP3—phosphatidylinositol (3,4,5)-triphosphate; PTEN—phosphatase and tensin homolog; RAS—Ras p21 protein activator 1 or RAS GTPase activating protein; REDD1—regulated in development and DNA damage responses; RHEB—Ras homologue expressed in brain; RTK—receptor tyrosine kinase; S6K—ribosomal protein S6 kinase; TSC—tuberous sclerosis complex; VEGF—vascular endothelial growth factor; VHL—von Hippel Lindau.

Mentions: Overexpression of the serine/threonine protein kinase mammalian target of rapamycin (mTOR) results from disruption of either TSC1 or TSC2. Typically, TSC1 and TSC2 form a complex, which inhibits Rheb (ras homologue expressed in brain), an activator of mTOR. The consequences of mTOR overexpression include abnormally rapid cell growth and hyperactivation of mRNA translation, which may lead to impaired synaptic plasticity in TSC [11] (Figure 1).


Plasticity and mTOR: towards restoration of impaired synaptic plasticity in mTOR-related neurogenetic disorders.

Gipson TT, Johnston MV - Neural Plast. (2012)

Pathways associated with neurogenetic conditions linked by mTOR and impaired synaptic plasticity. AKT-v—akt murine thymoma viral oncogene homolog 1; AMPK—adenosine monophosphate kinase; ATP—adenosine triphosphate; EIF4E/4EBP1—eukaryotic translation initiation factor 4E-binding protein 1; ERK—extracellular signal-related kinase; FKB12-FK506—binding protein family; FMRP—fragile X mental retardation protein; GBL/LST8—(mTOR-associated protein, LST8 homolog); GDP—guanosine diphosphate; GTP—guanosine triphosphate; GDP—guanosine diphosphate; HIF1α—hypoxia inducible factor 1, alpha subunit IGF—insulin-like growth factor; IGFR—insulin-like growth factor receptor; IRS—insulin receptor substrate; LKB1—serine threonine kinase 11; mTORC1—mammalian target of rapamycin complex 1; mTORC2—mammalian target of rapamycin complex 2; MEK—dual specificity mitogen-activated protein kinase 1; NF-1—neurofibromatosis 1; P/+ Thr308—phosphorylation of threonine, position 308; P/+ Ser473—phosphorylation of serine, position 473; PDK1—pyruvate dehydrogenase kinase, isozyme 1; PDK 2—pyruvate dehydrogenase kinase, isozyme 2; PI3K—phosphoinositide-3-kinase; PIKE—phosphoinositide 3-kinase enhancer; PIP1—p21-activated protein kinase-interacting protein 1 (PAK1 interacting protein 1); PIP2—phosphatidylinositol 4,5-biphosphate; PIP3—phosphatidylinositol (3,4,5)-triphosphate; PTEN—phosphatase and tensin homolog; RAS—Ras p21 protein activator 1 or RAS GTPase activating protein; REDD1—regulated in development and DNA damage responses; RHEB—Ras homologue expressed in brain; RTK—receptor tyrosine kinase; S6K—ribosomal protein S6 kinase; TSC—tuberous sclerosis complex; VEGF—vascular endothelial growth factor; VHL—von Hippel Lindau.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3350854&req=5

fig1: Pathways associated with neurogenetic conditions linked by mTOR and impaired synaptic plasticity. AKT-v—akt murine thymoma viral oncogene homolog 1; AMPK—adenosine monophosphate kinase; ATP—adenosine triphosphate; EIF4E/4EBP1—eukaryotic translation initiation factor 4E-binding protein 1; ERK—extracellular signal-related kinase; FKB12-FK506—binding protein family; FMRP—fragile X mental retardation protein; GBL/LST8—(mTOR-associated protein, LST8 homolog); GDP—guanosine diphosphate; GTP—guanosine triphosphate; GDP—guanosine diphosphate; HIF1α—hypoxia inducible factor 1, alpha subunit IGF—insulin-like growth factor; IGFR—insulin-like growth factor receptor; IRS—insulin receptor substrate; LKB1—serine threonine kinase 11; mTORC1—mammalian target of rapamycin complex 1; mTORC2—mammalian target of rapamycin complex 2; MEK—dual specificity mitogen-activated protein kinase 1; NF-1—neurofibromatosis 1; P/+ Thr308—phosphorylation of threonine, position 308; P/+ Ser473—phosphorylation of serine, position 473; PDK1—pyruvate dehydrogenase kinase, isozyme 1; PDK 2—pyruvate dehydrogenase kinase, isozyme 2; PI3K—phosphoinositide-3-kinase; PIKE—phosphoinositide 3-kinase enhancer; PIP1—p21-activated protein kinase-interacting protein 1 (PAK1 interacting protein 1); PIP2—phosphatidylinositol 4,5-biphosphate; PIP3—phosphatidylinositol (3,4,5)-triphosphate; PTEN—phosphatase and tensin homolog; RAS—Ras p21 protein activator 1 or RAS GTPase activating protein; REDD1—regulated in development and DNA damage responses; RHEB—Ras homologue expressed in brain; RTK—receptor tyrosine kinase; S6K—ribosomal protein S6 kinase; TSC—tuberous sclerosis complex; VEGF—vascular endothelial growth factor; VHL—von Hippel Lindau.
Mentions: Overexpression of the serine/threonine protein kinase mammalian target of rapamycin (mTOR) results from disruption of either TSC1 or TSC2. Typically, TSC1 and TSC2 form a complex, which inhibits Rheb (ras homologue expressed in brain), an activator of mTOR. The consequences of mTOR overexpression include abnormally rapid cell growth and hyperactivation of mRNA translation, which may lead to impaired synaptic plasticity in TSC [11] (Figure 1).

Bottom Line: This paper revealed significant similarities among the conditions.Not only do they share features of impaired synaptic plasticity and dysregulation of mTOR, but they also share clinical features--autism, intellectual disability, cutaneous lesions, and tumors.Although scientific advances towards discovery of effective treatment in some disorders have outpaced others, progress in understanding the signaling pathways that connect the entire group indicates that the lesser known disorders will become treatable as well.

View Article: PubMed Central - PubMed

Affiliation: Tuberous Sclerosis Center, Hugo Moser Research Institute, Kennedy Krieger Institute, Baltimore, MD 21205, USA. gipson@kennedykrieger.org

ABSTRACT

Objective: To review the recent literature on the clinical features, genetic mutations, neurobiology associated with dysregulation of mTOR (mammalian target of rapamycin), and clinical trials for tuberous sclerosis complex (TSC), neurofibromatosis-1 (NF1) and fragile X syndrome (FXS), and phosphatase and tensin homolog hamartoma syndromes (PTHS), which are neurogenetic disorders associated with abnormalities in synaptic plasticity and mTOR signaling.

Methods: Pubmed and Clinicaltrials.gov were searched using specific search strategies.

Results/conclusions: Although traditionally thought of as irreversible disorders, significant scientific progress has been made in both humans and preclinical models to understand how pathologic features of these neurogenetic disorders can be reduced or reversed. This paper revealed significant similarities among the conditions. Not only do they share features of impaired synaptic plasticity and dysregulation of mTOR, but they also share clinical features--autism, intellectual disability, cutaneous lesions, and tumors. Although scientific advances towards discovery of effective treatment in some disorders have outpaced others, progress in understanding the signaling pathways that connect the entire group indicates that the lesser known disorders will become treatable as well.

Show MeSH
Related in: MedlinePlus