Translating the Role of mTOR- and RAS-Associated Signalopathies in Autism Spectrum Disorder: Models, Mechanisms and Treatment
Abstract
:1. Introduction
1.1. The mTOR Pathway
1.2. The RAS Pathway
2. Clinical Phenotypes and Genetics
2.1. mTORopathies
2.1.1. Tuberous Sclerosis Complex
2.1.2. PTEN Hamartoma Tumor Syndrome
2.1.3. Additional Genetic Risk Factors of the mTOR Pathway
2.2. RASopathies
2.2.1. Neurofibromatosis Type 1
2.2.2. Legius Syndrome
2.2.3. Noonan Syndrome
2.2.4. Costello Syndrome
2.2.5. CFC Syndrome
2.2.6. RAS Pathway-Related Genetic Risk Factors
3. Animal Models
3.1. Animal Models of mTORopathies
3.1.1. TSC
3.1.2. PTEN
3.1.3. mTOR Hyperactivation Models
3.2. Animal Models of RASopathies
3.2.1. NF1
3.2.2. Legius Syndrome
3.2.3. Noonan Syndrome
3.2.4. CFC Syndrome
3.2.5. Costello Syndrome
3.2.6. SYNGAP1
4. Human Cell Models
4.1. Cell Models of mTORopathies
4.1.1. TSC
4.1.2. PTEN
4.1.3. DEPDC5
4.2. Cell Models of RASopathies
4.2.1. Neurofibromatosis Type 1
4.2.2. Noonan Syndrome
4.2.3. CFC Syndrome
4.2.4. Costello Syndrome
5. Pharmacological Interventions
5.1. mTORopathies
5.2. RASopathies
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Conflicts of Interest
Abbreviations
AMPAR | α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor |
ASD | Autism Spectrum Disorder; |
AKT | protein kinase B; |
BRAF | V-Raf murine sarcoma viral oncogene homolog B; |
Camp | cyclic adenosine monophosphate; |
CBL | Casitas B-lineage Lymphoma; |
CFCS | Cardiofacio-Cutaneous syndrome; |
CUL3 | Cullin 3; |
DEPDC5 | DEP domain containing 5 protein; |
EB | embryoid bodies; |
eIF4E | eukaryotic translation initiation factor 4E; |
EGFR | epidermal growth factor receptor; |
ERK 1/2 | extracellular signal-regulated kinase 1/2; |
ESC | embryonic stem cells; |
GABA | gamma-aminobutyric acid; |
GAP | GTPase activating protein; |
GATOR1 | GAP activity towards Rags 1; |
GEF | guanine nucleotide exchange factor; |
HCN | hyperpolarization activated cyclic nucleotide gated potassium and sodium channel; |
ID | Intellectual Disability; |
iPSC | induced pluripotent stem cells; |
iNeurons | induced Neurons; |
KO | knockout; |
KRAS | kirsten rat sarcoma virus proto-oncogene, GTPase; |
LAMTOR | also known as Ragulator, late endosomal/lysosomal adaptor and mitogen activated protein kinase and mechanistic target of rapamycin activator; |
LTP | Long-term potentiation; |
LTD | Long-term depression; |
LZTR1 | leucine zipper–like transcriptional regulator 1; |
MAF | minor allele frequency; |
MAP2K1/2 or MEK 1/2 | mitogen activated protein kinase 1/2; |
MEX3D | mex-3 RNA binding family member D; |
MGLURs | metabotropic glutamate receptors; |
MNK1/2 | MAPK-interacting kinase; |
MTORC1/2 | mammalian target of rapamycin complex 1/2; |
MWM | Morris water maze; |
NCT | National Clinical Trial number |
NF1 | Neurofibromatosis type 1; |
NMDA-R | N-methyl-D-aspartic acid receptor; |
NPC | neural progenitor cell; |
NPRL2 | nitrogen permease regulator 2-like protein; |
NRAS | neuroblastoma RAS viral oncogene homolog; |
NS | Noonan Syndrome; |
NSC | neural stem cell; |
PI3K | Phosphoinositide 3-Kinase; |
PTEN | Phosphatase and Tensin homolog; |
RAF1 | Raf-1 proto-oncogene, Serine/threonine kinase; |
Rag A/B, C/D | Ras-related GTP-binding protein A/B, C/D; |
Raptor | regulatory-associated protein of mTOR |
RHEB | Ras homolog enriched in brain; |
Rictor | rapamycin-insensitive companion of mTOR; |
RIT1 | Ras like without CAAX1; |
RPSK | ribosomal protein S6 kinase; |
RTK | receptor tyrosine kinases; |
SHOC2 | SHOC2 leucine rich repeat scaffold protein 2; |
SMAD1 | mothers against decapentaplegic homolog 1; |
SPRED1 | sprouty-related, EVH1 domain-containing protein 1 |
SYNGAP1 | synaptic Ras GTPase Activating Protein 1; |
SYNGAP1-ID | SYNGAP1-related intellectual disability; |
S6K1 | p70 S6 kinase 1; |
TSC | Tuberous Sclerosis Complex; |
4E-BP1 | eukaryotic translation initiation factor 4E-binding protein. |
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Clinical Phenotypes (Frequency) | Animal Models | Human Cell Models | Mutations in 10,000 ASD Cases [19] | |
---|---|---|---|---|
mTOR Pathway | ||||
TSC1-2 | Tuberous Sclerosis (1:10,000) ASD, ID, epilepsy, structural neurological changes, cancers/tumors, skin problems | Altered synaptic plasticity; altered social behavior; altered learning behavior and memory; disrupted neuronal cell development; seizures | Increased dendritic branching; altered synaptic plasticity; enlarged cell size | TSC1: n.d. TSC2: 3.8 |
PTEN | Cowden Syndrome (1:250,000) ASD, ID, epilepsy, structural neurological changes, cancers/tumors, skin problems | Altered synaptic plasticity; altered social behavior; altered learning behavior and memory; disrupted neuronal cell development; seizures | Impaired cortical folding | PTEN: 4.4 |
AKT1-3 | Cowden Syndrome (1–9:1,000,000) and AKT1-related Proteus Syndrome ASD, ID, epilepsy, structural neurological changes, cancers/tumors | Altered synaptic plasticity; altered social behavior; altered learning behavior and memory; disrupted neuronal cell development; seizures | Increased dendritic branching; altered synaptic plasticity; enlarged cell size | AKT1: n.d. AKT2: 1.3 AKT3: 1.3 |
MTOR | ASD, ID, epilepsy, structural neurological changes, cancers/tumors | Disrupted neuronal cell development; seizures | MTOR: 0.6 | |
RICTOR/RAPTOR | ASD, ID, epilepsy, structural neurological changes, cancers/tumors | Altered synaptic plasticity; disrupted neuronal cell development | RICTOR: n.d. RAPTOR: 2.5 | |
RHEB | ASD, ID, epilepsy, structural neurological changes, cancers/tumors | Altered synaptic plasticity; disrupted neuronal cell development; seizures | n.d. | |
S6K | ASD, ID, epilepsy, structural neurological changes, cancers/tumors, skin problems | Minor altered synaptic plasticity; altered learning behavior and memory; altered social behavior; disrupted neuronal cell development | RPS6KB1: 1.9 | |
eIF4EeIF4E-B | ASD, ID, epilepsy, structural neurological changes, cancers/tumors | Altered synaptic plasticity; altered social behavior; altered learning behavior and memory; disrupted neuronal cell development | EIF4B: 0.6 | |
DEPDC5 | ASD, ID, epilepsy, structural neurological changes, cancers/tumors | Altered synaptic plasticity; disrupted neuronal cell development; seizures | Enlarged cell size; increased proliferation rates | DEPDC5: 0.6 |
NPRL2 | ASD, ID, epilepsy, structural neurological changes, cancers/tumors | n.d | ||
RAS Pathway | ||||
SYNGAP1 | SYNGAP1-ID ASD, ID, epilepsy, schizophrenia | Altered synaptic plasticity (reduced hippocampal LTP and early spine maturation); elevated protein synthesis; altered spatial learning and memory, social novelty, fear memory and increased locomotor activity | SYNGAP1: 10.8 | |
NF1 | NF1 Syndrome (1: 3000): ASD, ID, structural neurological changes, congenital heart disease, bone malformations, cancers/tumors, skin problems | Altered synaptic plasticity (reduced hippocampal LTP and spine density); altered spatial learning and memory, social learning, attention and working memory deficits | Altered proliferation, apoptosis and neuronal differentiation | NF1: 4.4 |
SPRED1 | Legius Syndrome ASD, ID, structural neurological changes., congenital heart disease, skin problems | Altered synaptic plasticity (reduced hippocampal LTP), altered spatial learning and memory and social behavior | SPRED1: 0.6 | |
SOS1 | Noonan Syndrome (1:2000) ASD, ID, epilepsy, structural neurological changes, congenital heart disease, bone malformations, cancers/tumors | craniofacial abnormalities; cardiac defects | n.d. | |
CBL | Noonan Syndrome (1:2000) ASD, ID, epilepsy, structural neurological changes, congenital heart disease, bone malformations, cancers/tumors | CBL: 0.6 | ||
HRAS | Costello Syndrome (1:300,000–1.25 mil.) ASD, ID, structural neurological changes, congenital heart disease, bone malformations, cancers/tumors, skin problems | Increased soma size and spine complexity: enhanced LTP; altered spatial learning and memory and contextual fear conditioning | Increased astrogenesis, increased proteoglycans, dysregulated cortical maturation | n.d. |
NRAS | Noonan Syndrome (1:2000) ASD, ID, epilepsy, structural neurological changes, congenital heart disease, bone malformations, cancers/tumors | Leukemias, craniofacial abnormalities, cardiac defects | n.d. | |
KRAS | CFC and Noonan Syndrome ASD, ID, epilepsy, structural neurological changes, congenital heart disease, bone malformations, cancers/tumors | Altered synaptic plasticity (reduced hippocampal LTP); elevated protein synthesis; altered spatial learning and memory, working memory; normal social behaviors | KRAS: 0.6 | |
RIT1 | Noonan Syndrome (1:2000) ASD, ID, epilepsy, structural neurological changes, congenital heart disease, bone malformations, cancers/tumors | Reduced dendritic length and complexity | n.d. | |
RAF1 | Noonan Syndrome (1:2000) ASD, ID, epilepsy, structural neurological changes, congenital heart disease, bone malformations, cancers/tumors | Increased astroglial cell density; enhanced spatial learning and memory | n.d. | |
BRAF | CFC and Noonan Syndrome ASD, ID, epilepsy, structural neurological changes, congenital heart disease, bone malformations, cancers/tumors | Altered synaptic plasticity (reduced hippocampal LTP); altered spatial learning and memory; seizures | Inhibited neuronal differentiation; premature differentiation and impaired cortical layering | BRAF: 1.3 |
MEK1/2 | CFC Syndrome (1:800,000) ASD, ID, epilepsy, structural neurological changes, congenital heart disease, bone malformations, cancers/tumors | Increased astroglial cells, neuronal loss; altered spatial learning and memory; altered fear conditioning; craniofacial abnormalities | MAP2K1: 0.6MAP2K2: 1.3 | |
PTPN11 (SHP2) | Noonan Syndrome (1:2000) ASD, ID, epilepsy, structural neurological changes, congenital heart disease, bone malformations, cancers/tumors | Altered synaptic plasticity; altered spatial learning and memory; increased hyperactivity, reduced anxiety behavior | Inhibited differentiation, increased gliogenesis; reduced neurite outgrowth; lower spontaneous firing rate | PTPN11: 1.3 |
LZTR1 | Noonan Syndrome (1:2000) | LZTR1: 3.2 |
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Vasic, V.; Jones, M.S.O.; Haslinger, D.; Knaus, L.S.; Schmeisser, M.J.; Novarino, G.; Chiocchetti, A.G. Translating the Role of mTOR- and RAS-Associated Signalopathies in Autism Spectrum Disorder: Models, Mechanisms and Treatment. Genes 2021, 12, 1746. https://doi.org/10.3390/genes12111746
Vasic V, Jones MSO, Haslinger D, Knaus LS, Schmeisser MJ, Novarino G, Chiocchetti AG. Translating the Role of mTOR- and RAS-Associated Signalopathies in Autism Spectrum Disorder: Models, Mechanisms and Treatment. Genes. 2021; 12(11):1746. https://doi.org/10.3390/genes12111746
Chicago/Turabian StyleVasic, Verica, Mattson S. O. Jones, Denise Haslinger, Lisa S. Knaus, Michael J. Schmeisser, Gaia Novarino, and Andreas G. Chiocchetti. 2021. "Translating the Role of mTOR- and RAS-Associated Signalopathies in Autism Spectrum Disorder: Models, Mechanisms and Treatment" Genes 12, no. 11: 1746. https://doi.org/10.3390/genes12111746