mTOR Signaling in Growth, Metabolism, and Disease

Cell, Год журнала: 2017, Номер 168(6), С. 960 - 976

Опубликована: Март 1, 2017

Язык: Английский

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AKT/PKB Signaling: Navigating the Network

Cell, Год журнала: 2017, Номер 169(3), С. 381 - 405

Опубликована: Апрель 1, 2017

Язык: Английский

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mTOR at the nexus of nutrition, growth, ageing and disease

Nature Reviews Molecular Cell Biology, Год журнала: 2020, Номер 21(4), С. 183 - 203

Опубликована: Янв. 14, 2020

Язык: Английский

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Advancing the understanding of autism disease mechanisms through genetics

Nature Medicine, Год журнала: 2016, Номер 22(4), С. 345 - 361

Опубликована: Апрель 1, 2016

Язык: Английский

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Neurodevelopmental Disorders: From Genetics to Functional Pathways

Trends in Neurosciences, Год журнала: 2020, Номер 43(8), С. 608 - 621

Опубликована: Июнь 5, 2020

NDDs are caused by the disruption of essential neurodevelopmental processes. Many genes and mutations associated with NDDs, pointing to a heterogeneous origin these disorders.Genotype–phenotype correlations difficult establish due existence multiple genetic as well environmental factors that influence phenotypical outcome. The two-hit model molecular diagnoses important should be taken into account when addressing NDDs.Most known belong few common frequently affected pathways. Functional studies elucidating how different can disturb converging pathways lead identification potential targets, thereby opening perspectives for future treatment. Neurodevelopmental disorders (NDDs) class affecting brain development function characterized wide clinical variability. In this review, we discuss presentation particular attention gene vulnerability, mutational load, model. Despite complex architecture events various proteins involved appear converge on pathways, such synaptic plasticity/function, chromatin remodelers mammalian target rapamycin (mTOR) pathway. A thorough understanding mechanisms behind will hopefully candidates could targeted treatment approaches. an inability reach cognitive, emotional, motor developmental milestones. Typically, tightly coordinated development. constitute serious health problem in our society, >3% children worldwide [1.Gilissen C. et al.Genome sequencing identifies major causes severe intellectual disability.Nature. 2014; 511: 344-347Crossref PubMed Scopus (573) Google Scholar]. They have etiology impaired cognition, communication, adaptive behavior, psychomotor skills. include autism spectrum disorder (ASD), disability (ID), deficit hyperactivity disorder, epilepsy [2.Niemi M.E.K. al.Common variants contribute risk rare disorders.Nature. 2018; 562: 268-271Crossref (63) Scholar,3.Tărlungeanu D.C. Novarino G. Genomics disorders: avenue personalized medicine.Exp. Mol. Med. 50: 1-7Crossref (5) suggested shared signs characterize [4.Cristino A.S. al.Neurodevelopmental neuropsychiatric represent interconnected system.Mol. Psychiatry. 19: 294-301Crossref (103) Scholar,5.Hormozdiari F. al.The discovery integrated networks related disorders.Genome Res. 2015; 25: 142-154Crossref (123) Accordingly, comorbidity (see Glossary) two or more is observed. For instance, combination ID, ASD, commonly reported individual patients [6.van Bokhoven H. Genetic epigenetic disabilities.Annu. Rev. Genet. 2011; 45: 81-104Crossref (203) Scholar,7.Du X. al.Genetic diagnostic evaluation trio-based whole exome among diagnosed suspected disorder.Front. 9: 594Crossref Identification pathogenic help explain aforementioned eventually effective terms genetics, types mutation been including chromosomal rearrangements, copy number variations, small indels, point mutations. Thus, underlying event, diagnosis, challenging task needs overcome heterogeneity array variations. Some technologies currently used diagnosis summarized Box 1.Box 1Evolution Diagnostic Flowchart NDDsEarly NDD counseling, patient management, medical intervention.Previously, G banded karyotype FMR1 trinucleotide repeat analysis were recommended first-tier test unexplained NDDs. However, yield was low [111.Blesson A. Cohen J.S. counseling disorders.Cold Spring Harb. Perspect. 2019; 10: a036533Google breakthrough next-generation has led significant advancements Scholar,112.Carneiro T.N. al.Utility elucidation basis isolated syndromic disability: illustrative cases.Appl. Clin. 11: 93-98Crossref (7) To date, >900 responsible X-linked, autosomal dominant, recessive [113.Chiurazzi P. Pirozzi Advances - disability.F1000Res. 2016; 5 (Faculty Rev-599): F1000Crossref (37) Scholar,114.Wright C.F. DDD study: scalable genome-wide research data.Lancet. 385: 1305-1314Abstract Full Text PDF (315) Due correlation protein-coding genes, cheaper quicker whole-exome (WES) preferred tool informative whole-genome [115.Clark M.M. al.Meta-analysis utility genome microarray diseases.NPJ Genom. 3: 16Crossref (71) Scholar,116.Srivastava S. multidisciplinary consensus statement: individuals disorders.Genet. 21: 2413-2421Abstract (32) Different highlighted efficiency tool, having up >40% especially both biological parents considered Scholar] Still, also occur noncoding regions, regulatory elements, alter expression levels DNA microarrays detect gross aberrations otherwise not detectable conventional WES [117.Martin C.L. Ledbetter D.H. Chromosomal testing disorders.JAMA. 2017; 317: 2545-2546Crossref Scholar,118.Bhattacharya S.K. al.Chromosomal uncovers variations congenital anomalies.J. Biomed. Sci. 8: 3Google expected estimated ~10–20% distinct Epigenetic alterations, escaping detection, observed presence Therefore, additional methods changes, PCR, tandem mass spectrometry, southern blot. Early intervention. Previously, These challenges notwithstanding, recognition NDD-causing crucial accurate represents first step toward better disorders. This review focuses starting from genetics moving functional level. First, study familial cases improved Second, consider determine phenotype, diagnoses. We highlight relevance context Finally, debate whether cellular allows circumventing issue variability open treatments. vital onset delineation genotype–phenotype monitor progress foresee complications. numerous NDD-causative identified, many still do receive diagnosis. Additionally, phenotype–genotype brought light severity vary substantially overlapping [8.Li Y. al.Genotype phenotype SHANK3 de novo disorders.Am. J. 176: 2668-2676PubMed Scholar,9.Casanova E.L. al.Widespread genotype-phenotype disability.Front. 9535–535Crossref missing heritability multifactorial and/or polygenic nature Familial useful paradigm dissecting contribution nongenetic pathogenesis background. reason, conducted monozygotic twins discordant phenotypes [10.Huang al.Identifying genomic using sequencing.Mol. Ther. Nucleic Acids. 14: 204-211Abstract (4) Scholar, 11.Willfors al.Medical history etiologies autism.Transl. 7e1014Crossref (10) 12.Radley J.A. al.Deep phenotyping 14 new IQSEC2 variants, phenotype.Clin. 95: 496-506Crossref pedigrees where incomplete penetrance offspring [13.Karaca E. al.Phenotypic expansion illuminates multilocus variation.Genet. 20: 1528-1537Abstract (33) line tremendous only mere disease, but protective factors. Furthermore, it establishing correlations. Thanks inherited emerged outcome essentially revolves around main principles: vulnerability load (Figure 1A ). Gene defined capability given tolerate disruptive variants: lower tolerance towards mutations, higher level vulnerability. haploinsufficient striking dosage sensitivity. fall within category highly vulnerable disease risk. Examples DEPDC5, CACNA1A, SCN8A, which discussed later section. Disruption one high probability inducing absence other causative events, thus resulting monogenic forms [14.Iossifov I. al.Low their biased transmission.Proc. Natl. Acad. U. 112: E5600-E5607Crossref (58) normally subject strong negative selective pressure. Hence, population recognized reduced compared loci words, categorized penetrance. end comprises those less sensitive Variants under pressure transmitted families generations Scholar,14.Iossifov Since single nonvulnerable causing per se, they Nonetheless, recent demonstrated portion attributed Scholar,15.Kurki M.I. al.Contribution sub-isolate Northern Finland.Nat. Commun. 410Crossref (6) fact, additive effects result Scholar,16.Pizzo L. al.Rare background modulate cognitive carrying disease-associated variants.Genet. 816-825Abstract (26) cases, however, depends sum physical interactions between (i.e., epistasis) [17.Mitra al.Reverse pathway approach epistasis disorders.PLoS 13e1006516Crossref (19) Scholar,18.Iyer al.Pervasive defects autism-associated 16p11.2 deletion Drosophila melanogaster.Nat. 2548Crossref (13) Epistatic sensitivity strongly correlate concept argues complexity influenced events. example, loss-of-function monoallelic sodium channels CACNA1A SCN8A variety features movement benign infantile seizures 1B) [19.Reinson K. al.Biallelic cause early epileptic encephalopathy progressive cerebral, cerebellar, optic nerve atrophy.Am. 170: 2173-2176Crossref Scholar,20.Wengert E.R. SCN8A-related encephalopathy.Epilepsia. 60: 2277-2285Crossref (2) accordance criteria germline biallelic changes 1C) recently compound heterozygous probands encephalopathy, while siblings exhibit mild impairment without seizure might determined somatic mechanism classic hypothesis, constitutive generates subsequent hit occurring during then already present 1E). One example comes DEPDC5. Germline DEPDC5 refractory focal epilepsies [21.Ribierre T. al.Second-hit mosaic mTORC1 repressor cortical dysplasia-associated epilepsy.J. Investig. 128: 2452-2458Crossref (0) second variant inactivation found dysplasia Scholar,22.Lee W.S. limited dysmorphic neurons type IIA.Ann. Transl. Neurol. 6: 1338-1344Crossref (1) Primary secondary at each other, expanding hypothesis 1D). Several unveiled Scholar,23.Guo al.Inherited autism/developmental delay suggest model.Mol. Autism. 64Crossref (16) 24.Posey J.E. al.Resolution variation.N. Engl. 376: 21-31Crossref (246) 25.Liu al.Reanalysis data.N. 380: 2478-2480Crossref notion analyses established likely [23.Guo disrupting positively correlates Scholar,24.Posey dissected intrafamilial families, explained severely cumulative makes pathological 1F). burden correlated predisposition educational attainment ID data available literature purely exception rather than rule. Most most nature, hence confirming broad Importantly, factors, although discussion beyond scope current review. implementation (NGS) flowchart dramatically increased percentage who ramifications since assessment recurrence gives possibility advances field served roadmap aimed As next, elucidated some offers opportunity complexities variability, develop therapeutic performed past decade shown affect role conserved [26.Sahin M. Sur Genes, circuits, precision therapies disorders.Science. 350aab3897Crossref (108) 27.Parikshak N.N. al.Integrative

Язык: Английский

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Molecular neurobiology of mTOR

Neuroscience, Год журнала: 2016, Номер 341, С. 112 - 153

Опубликована: Ноя. 23, 2016

Mammalian/mechanistic target of rapamycin (mTOR) is a serine-threonine kinase that controls several important aspects mammalian cell function. mTOR activity modulated by various intra- and extracellular factors; in turn, changes rates translation, transcription, protein degradation, signaling, metabolism, cytoskeleton dynamics. has been repeatedly shown to participate neuronal development the proper functioning mature neurons. Changes are often observed nervous system diseases, including genetic diseases (e.g., tuberous sclerosis complex, Pten-related syndromes, neurofibromatosis, Fragile X syndrome), epilepsy, brain tumors, neurodegenerative disorders (Alzheimer's disease, Parkinson's Huntington's disease). Neuroscientists only recently began deciphering molecular processes downstream function system. As result, we gaining knowledge about ways which aberrant lead diseases. In this review, provide comprehensive view system, with special focus on functions control autophagy) likely underlie contribution

Язык: Английский

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Mitochondria as central regulators of neural stem cell fate and cognitive function

Nature reviews. Neuroscience, Год журнала: 2018, Номер 20(1), С. 34 - 48

Опубликована: Ноя. 21, 2018

Язык: Английский

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Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Окт. 2, 2023

The mammalian target of rapamycin (mTOR) is a protein kinase that controls cellular metabolism, catabolism, immune responses, autophagy, survival, proliferation, and migration, to maintain homeostasis. mTOR signaling cascade consists two distinct multi-subunit complexes named complex 1/2 (mTORC1/2). catalyzes the phosphorylation several critical proteins like AKT, C, insulin growth factor receptor (IGF-1R), 4E binding 1 (4E-BP1), ribosomal S6 (S6K), transcription EB (TFEB), sterol-responsive element-binding (SREBPs), Lipin-1, Unc-51-like autophagy-activating kinases. plays central role in regulating translation, lipid synthesis, nucleotide biogenesis lysosomes, nutrient sensing, signaling. emerging pieces evidence have revealed constitutive activation pathway due mutations/amplification/deletion either its (mTORC1 mTORC2) or upstream targets responsible for aging, neurological diseases, human malignancies. Here, we provide detailed structure mTOR, complexes, comprehensive regulators, as well downstream effectors cascades biomolecules, autophagy. Additionally, summarize potential long noncoding RNAs (lncRNAs) an important modulator Importantly, highlighted disorders, cancers, cancer stem cells, drug resistance. discuss developments therapeutic targeting with improved anticancer efficacy benefit patients clinics.

Язык: Английский

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The mTOR signalling cascade: paving new roads to cure neurological disease

Nature Reviews Neurology, Год журнала: 2016, Номер 12(7), С. 379 - 392

Опубликована: Июнь 24, 2016

Язык: Английский

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The Circadian Protein BMAL1 Regulates Translation in Response to S6K1-Mediated Phosphorylation

Cell, Год журнала: 2015, Номер 161(5), С. 1138 - 1151

Опубликована: Май 1, 2015

Язык: Английский

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