MTOR Signalling Pathway - A Root Cause for Idiopathic Autism?

Overview

Journal BMB Rep

Specialties Biochemistry
Molecular Biology

Date 2019 Jun 13

PMID 31186084

Citations 32

Authors

Harsha Ganesan

Venkatesh Balasubramanian

Mahalaxmi Iyer

Anila Venugopal

Mohana Devi Subramaniam

Ssang-Goo Cho

Balachandar Vellingiri

Affiliations

Soon will be listed here.

Abstract

Autism spectrum disorder (ASD) is a complex neurodevelopmental monogenic disorder with a strong genetic influence. Idiopathic autism could be defined as a type of autism that does not have a specific causative agent. Among signalling cascades, mTOR signalling pathway plays a pivotal role not only in cell cycle, but also in protein synthesis and regulation of brain homeostasis in ASD patients. The present review highlights, underlying mechanism of mTOR and its role in altered signalling cascades as a triggering factor in the onset of idiopathic autism. Further, this review discusses how distorted mTOR signalling pathway stimulates truncated translation in neuronal cells and leads to downregulation of protein synthesis at dendritic spines of the brain. This review concludes by suggesting downstream regulators such as p70S6K, eIF4B, eIF4E of mTOR signalling pathway as promising therapeutic targets for idiopathic autistic individuals. [BMB Reports 2019; 52(7): 424-433].

Citing Articles

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Circadian desynchrony in early life leads to enduring autistic-like behavioral changes in adulthood.

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References

OLoghlen A, Perez-Morgado M, Salinas M, Martin M . N-acetyl-cysteine abolishes hydrogen peroxide-induced modification of eukaryotic initiation factor 4F activity via distinct signalling pathways. Cell Signal. 2005; 18(1):21-31. DOI: 10.1016/j.cellsig.2005.03.013. View

Panner A, James C, Berger M, Pieper R . mTOR controls FLIPS translation and TRAIL sensitivity in glioblastoma multiforme cells. Mol Cell Biol. 2005; 25(20):8809-23. PMC: 1265779. DOI: 10.1128/MCB.25.20.8809-8823.2005. View

Tavazoie S, Alvarez V, Ridenour D, Kwiatkowski D, Sabatini B . Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2. Nat Neurosci. 2005; 8(12):1727-34. DOI: 10.1038/nn1566. View

Kwon C, Luikart B, Powell C, Zhou J, Matheny S, Zhang W . Pten regulates neuronal arborization and social interaction in mice. Neuron. 2006; 50(3):377-88. PMC: 3902853. DOI: 10.1016/j.neuron.2006.03.023. View

Ogawa S, Kwon C, Zhou J, Koovakkattu D, Parada L, Sinton C . A seizure-prone phenotype is associated with altered free-running rhythm in Pten mutant mice. Brain Res. 2007; 1168:112-23. DOI: 10.1016/j.brainres.2007.06.074. View

Choi Y, Di Nardo A, Kramvis I, Meikle L, Kwiatkowski D, Sahin M . Tuberous sclerosis complex proteins control axon formation. Genes Dev. 2008; 22(18):2485-95. PMC: 2546692. DOI: 10.1101/gad.1685008. View

Kelleher 3rd R, Bear M . The autistic neuron: troubled translation?. Cell. 2008; 135(3):401-6. DOI: 10.1016/j.cell.2008.10.017. View

Xiao Z, Casey K, Jameson S, Curtsinger J, Mescher M . Programming for CD8 T cell memory development requires IL-12 or type I IFN. J Immunol. 2009; 182(5):2786-94. PMC: 2648124. DOI: 10.4049/jimmunol.0803484. View

Zhao X, Gartenhaus R . Phospho-p70S6K and cdc2/cdk1 as therapeutic targets for diffuse large B-cell lymphoma. Expert Opin Ther Targets. 2009; 13(9):1085-93. DOI: 10.1517/14728220903103833. View

10.

Laplante M, Sabatini D . mTOR signaling at a glance. J Cell Sci. 2009; 122(Pt 20):3589-94. PMC: 2758797. DOI: 10.1242/jcs.051011. View

11.

Hutsler J, Zhang H . Increased dendritic spine densities on cortical projection neurons in autism spectrum disorders. Brain Res. 2009; 1309:83-94. DOI: 10.1016/j.brainres.2009.09.120. View

12.

Sharma A, Hoeffer C, Takayasu Y, Miyawaki T, McBride S, Klann E . Dysregulation of mTOR signaling in fragile X syndrome. J Neurosci. 2010; 30(2):694-702. PMC: 3665010. DOI: 10.1523/JNEUROSCI.3696-09.2010. View

13.

Osborne L . Caveat mTOR: aberrant signaling disrupts corticogenesis. J Clin Invest. 2010; 120(5):1392-5. PMC: 2860937. DOI: 10.1172/JCI43030. View

14.

Dowling R, Topisirovic I, Alain T, Bidinosti M, Fonseca B, Petroulakis E . mTORC1-mediated cell proliferation, but not cell growth, controlled by the 4E-BPs. Science. 2010; 328(5982):1172-6. PMC: 2893390. DOI: 10.1126/science.1187532. View

15.

Oblak A, Gibbs T, Blatt G . Decreased GABA(B) receptors in the cingulate cortex and fusiform gyrus in autism. J Neurochem. 2010; 114(5):1414-23. PMC: 2923229. DOI: 10.1111/j.1471-4159.2010.06858.x. View

16.

Kanne S, Gerber A, Quirmbach L, Sparrow S, Cicchetti D, Saulnier C . The role of adaptive behavior in autism spectrum disorders: implications for functional outcome. J Autism Dev Disord. 2010; 41(8):1007-18. DOI: 10.1007/s10803-010-1126-4. View

17.

Feliciano D, Su T, Lopez J, Platel J, Bordey A . Single-cell Tsc1 knockout during corticogenesis generates tuber-like lesions and reduces seizure threshold in mice. J Clin Invest. 2011; 121(4):1596-607. PMC: 3069783. DOI: 10.1172/JCI44909. View

18.

Gatto C, Broadie K . Genetic controls balancing excitatory and inhibitory synaptogenesis in neurodevelopmental disorder models. Front Synaptic Neurosci. 2011; 2:4. PMC: 3059704. DOI: 10.3389/fnsyn.2010.00004. View

19.

Mattila M, Kielinen M, Linna S, Jussila K, Ebeling H, Bloigu R . Autism spectrum disorders according to DSM-IV-TR and comparison with DSM-5 draft criteria: an epidemiological study. J Am Acad Child Adolesc Psychiatry. 2011; 50(6):583-592.e11. DOI: 10.1016/j.jaac.2011.04.001. View

20.

Jernigan C, Goswami D, Austin M, Iyo A, Chandran A, Stockmeier C . The mTOR signaling pathway in the prefrontal cortex is compromised in major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2011; 35(7):1774-9. PMC: 3154612. DOI: 10.1016/j.pnpbp.2011.05.010. View