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mTORopathy in Human Genetic disorders: Heritable Autism Spectrum Disorders
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Sahar Fanoudi   |
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Abstract: (195 Views) |
Introduction: Autism spectrum disorder (ASD) is defined as a diverse group of pervasive developmental disorders (PDDs) of neurodevelopmental origin characterized by the lack of social interaction skills, difficulty in communication, restricted and repetitive interests or behaviors that show an early onset in childhood, starting at birth, and remain throughout adulthood resulting in lifetime persisting disabilities. Several ASDs with causal mutations in known genetic loci have evidence of mTOR and autophagy involvement including Rett syndrome, neurofibromatosis 1, and fragile X syndrome.
- Rett Syndrome
Rett syndrome is a neurological impairment caused by mutation in the gene methyl-CpG-binding protein 2 (MECP2). MECP2 is an X-linked gene that results in lethal neonatal encephalopathy in males, but not in females who mature to develop Rett syndrome. Hypothesizing that aberrations in neuronal protein synthesis contribute to ASD, Ricciardi et al. investigated the AKT/mTOR pathway in a Rett syndrome murine model. Immunohistochemistry showed a reduction of ribosomal protein S6 in Mecp2 mutant mice at 8 weeks. Closer examination during development in various brain regions revealed a decrease in protein synthesis, attributed to aberrant Akt/mTOR signaling. Western blot analysis of the p70-S6K revealed that phosphorylation suppressed mTOR signaling as well as Akt in the brain.
- Neurofibromatosis Type 1
Neurofibromatosis type 1 is a commonly occurring autosomal dominant disorder by a mutation to the neurofibromin gene (NF1) located on chromosome 17q11.2. The intellectual impairment in NF1 is accompanied by social, emotional, and developmental deficits typical of ASD. The investigators confirmed that rapamycin could normalize ribosomal S6 aggregates in vivo and promote normal astrocyte proliferation, indicating that rapalogs should be further examined to treat neurofibromatosis.
- Fragile X Syndrome
Fragile X syndrome is the leading cause of heritable autism. The loss of function of FMR1 (fragile X mental retardation-1) activates PI3K via PI3K enhancer resulting in mTOR activation. Research findings have sparked interest in utilizing glutamate, GABA, and/or mTOR signaling pathways as therapeutic targets. With the prevalence of ASDs reaching 1 in 68 children (1 in 42 boys and 1 in 189 girls) scientists will continue to explore the molecular complexities and involvement of mTOR signaling and autophagy in autism.
- mTORopathy: Tuberous Sclerosis and Genetic Epilepsy
Tuberous sclerosis is a phakomatosis (or neurocutaneous disorder) named for the cortical tubers which constitute one of three types of TSC-associated benign brain tumors. The major clinical features of tuberous sclerosis can also include facial angiofibromas, non-traumatic ungula, hypomelanotic macules, shagreen patches, retinal nodular hamartomas or achromic patches, cardiac rhabdomyoma, lymphangiomyomatosis, renal angiomyolipoma, bone cysts, or hamartomatous rectal polyps. Twenty to sixty percent of TSC cases are associated with ASDs which accounts for 1-4% of autism cases, reduced intellectual quotient (30% very low), and psychiatric disorders. Epilepsy occurs in about 80% of TSC patients, the most common CNS manifestation, as well as infantile spasms 50%. Tang and others used an autistic mouse (TSC2 deficient, Tsc2+/-) to study mTOR. In this mouse model, mTOR is constitutively overactivated and results in postnatal spine pruning defects. |
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| Keywords: Autism spectrum disorder (ASD), mTOR signaling |
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Full-Text [PDF 277 kb]
(28 Downloads)
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Type of Study: Research |
Subject:
General
Received: 2024/03/4 | Accepted: 2023/08/10 | Published: 2023/08/10
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