scholarly journals Proteomics of autism and Alzheimer’s mouse models reveal common alterations in mTOR signaling pathway

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shira Mencer ◽  
Maryam Kartawy ◽  
Felix Lendenfeld ◽  
Huda Soluh ◽  
Manish Kumar Tripathi ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Mouse Models ◽  
Neurological Disorders ◽  
Large Scale ◽  
Molecular Mechanisms ◽  
Mammalian Target Of Rapamycin ◽  
Autism Spectrum ◽  
Novel Therapy ◽  
Western Blots ◽  
Mtorc1 Signaling

AbstractAutism spectrum disorder (ASD) and Alzheimer’s disease (AD) are two different neurological disorders that share common clinical features, such as language impairment, executive functions, and motor problems. A genetic convergence has been proposed as well. However, the molecular mechanisms of these pathologies are still not well understood. Protein S-nitrosylation (SNO), the nitric oxide (NO)-mediated posttranslational modification, targets key proteins implicated in synaptic and neuronal functions. Previously, we have shown that NO and SNO are involved in the InsG3680(+/+) ASD and P301S AD mouse models. Here, we performed large-scale computational biology analysis of the SNO-proteome followed by biochemical validation to decipher the shared mechanisms between the pathologies. This analysis pointed to the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway as one of the shared molecular mechanisms. Activation of mTOR in the cortex of both mouse models was confirmed by western blots that showed increased phosphorylation of RPS6, a major substrate of mTORC1. Other molecular alterations affected by SNO and shared between the two mouse models, such as synaptic-associated processes, PKA signaling, and cytoskeleton-related processes were also detected. This is the first study to decipher the SNO-related shared mechanisms between SHANK3 and MAPT mutations. Understanding the involvement of SNO in neurological disorders and its intersection between ASD and AD might help developing an effective novel therapy for both neuropathologies.

scholarly journals AMP-Activated Protein Kinase as a Key Trigger for the Disuse-Induced Skeletal Muscle Remodeling

2018 ◽  
Vol 19 (11) ◽  
pp. 3558 ◽  
Author(s):  
Natalia Vilchinskaya ◽  
Igor Krivoi ◽  
Boris Shenkman
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Histone Deacetylases ◽  
Molecular Mechanisms ◽  
Weight Bearing ◽  
Mammalian Target Of Rapamycin ◽  
Adenosine Monophosphate ◽  
Chain Gene ◽  
Mtorc1 Signaling ◽  
The Impact

Molecular mechanisms that trigger disuse-induced postural muscle atrophy as well as myosin phenotype transformations are poorly studied. This review will summarize the impact of 5′ adenosine monophosphate -activated protein kinase (AMPK) activity on mammalian target of rapamycin complex 1 (mTORC1)-signaling, nuclear-cytoplasmic traffic of class IIa histone deacetylases (HDAC), and myosin heavy chain gene expression in mammalian postural muscles (mainly, soleus muscle) under disuse conditions, i.e., withdrawal of weight-bearing from ankle extensors. Based on the current literature and the authors’ own experimental data, the present review points out that AMPK plays a key role in the regulation of signaling pathways that determine metabolic, structural, and functional alternations in skeletal muscle fibers under disuse.

scholarly journals Electroacupuncture Reduces Weight in Diet-Induced Obese Rats via Hypothalamic Tsc1 Promoter Demethylation and Inhibition of the Activity of mTORC1 Signaling Pathway

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Jincheng Leng ◽  
Feng Xiong ◽  
Junpeng Yao ◽  
Xiahuan Dai ◽  
Yulei Luo ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Body Fat ◽  
Mammalian Target Of Rapamycin ◽  
Gene Promoter ◽  
Chow Group ◽  
Diet Group ◽  
The Body ◽  
Sprague Dawley ◽  
Tsc1 Gene ◽  
Mtorc1 Signaling

Subject. The study aimed to investigate the mechanism of electroacupuncture reducing weight via tuberous sclerosis complex 1 (Tsc1) promoter methylation, inhibiting the mammalian target of rapamycin complex 1 (mTORC1) pathway. Materials and Methods. Male Sprague-Dawley rats were divided into chow-fed group (chow group) or high-fat diet group (HF group) for 14 weeks. The obesity rats in HF group were randomly divided into electroacupuncture group (EA group) and diet-induced obesity (DIO) group, which received EA stimulation on bilateral ST25, RN12, SP6, and ST36 for 4 weeks or no further treatment, respectively. Methylation of the Tsc1 gene promoter and expression of agouti-related protein (AgRP), neuropeptide Y (NPY), and proopiomelanocortin (PoMC) were detected at the 18th week. Results. At week 18, weight, body fat, and the body fat rate in DIO group were significantly higher than those of the chow and EA group. Compared with the chow group, the DIO group had increased methylation of the Tsc1 gene promoter and expression of mTORC1, AgRP, and NPY gene and decreased PoMC in the hypothalamus; after EA, methylation of the Tsc1 gene promoter, mRNA, and protein of the mTORC1 and expression of AgRP and NPY gene decreased and PoMC increased significantly. Conclusions. Our study could shed light on the potential pathway where EA exerts effects on the mechanism of EA treatment for obesity through the hypothalamic Tsc1 promoter demethylation and inhibition of the activity of mTORC1 signaling pathway.

scholarly journals SLC36A1-mTORC1 signaling drives acquired resistance to CDK4/6 inhibitors

2019 ◽  
Vol 5 (9) ◽  
pp. eaax6352 ◽  
Author(s):  
Akihiro Yoshida ◽  
Yiwen Bu ◽  
Shuo Qie ◽  
John Wrangle ◽  
E. Ramsay Camp ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Fragile X ◽  
Acquired Resistance ◽  
Mammalian Target Of Rapamycin ◽  
Cyclin Dependent Kinase ◽  
Solute Carrier Family ◽  
Potential Therapeutic Target ◽  
Mtorc1 Signaling ◽  
Solute Carrier

The cyclin-dependent kinase 4/6 (CDK4/6) kinase is dysregulated in melanoma, highlighting it as a potential therapeutic target. CDK4/6 inhibitors are being evaluated in trials for melanoma and additional cancers. While beneficial, resistance to therapy is a concern, and the molecular mechanisms of such resistance remain undefined. We demonstrate that reactivation of mammalian target of rapamycin 1 (mTORC1) signaling through increased expression of the amino acid transporter, solute carrier family 36 member 1 (SLC36A1), drives resistance to CDK4/6 inhibitors. Increased expression of SLC36A1 reflects two distinct mechanisms: (i) Rb loss, which drives SLC36A1 via reduced suppression of E2f; (ii) fragile X mental retardation syndrome–associated protein 1 overexpression, which promotes SLC36A1 translation and subsequently mTORC1. Last, we demonstrate that a combination of a CDK4/6 inhibitor with an mTORC1 inhibitor has increased therapeutic efficacy in vivo, providing an important avenue for improved therapeutic intervention in aggressive melanoma.

scholarly journals Regulation of common neurological disorders by gut microbial metabolites

2021 ◽  
Author(s):  
Jeongho Park ◽  
Chang H. Kim
Keyword(s):  
Neurological Disorders ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Short Chain Fatty Acids ◽  
Autism Spectrum ◽  
Molecular Networks ◽  
Microbial Metabolites ◽  
Cns Diseases ◽  
The Impact

AbstractThe gut is connected to the CNS by immunological mediators, lymphocytes, neurotransmitters, microbes and microbial metabolites. A mounting body of evidence indicates that the microbiome exerts significant effects on immune cells and CNS cells. These effects frequently result in the suppression or exacerbation of inflammatory responses, the latter of which can lead to severe tissue damage, altered synapse formation and disrupted maintenance of the CNS. Herein, we review recent progress in research on the microbial regulation of CNS diseases with a focus on major gut microbial metabolites, such as short-chain fatty acids, tryptophan metabolites, and secondary bile acids. Pathological changes in the CNS are associated with dysbiosis and altered levels of microbial metabolites, which can further exacerbate various neurological disorders. The cellular and molecular mechanisms by which these gut microbial metabolites regulate inflammatory diseases in the CNS are discussed. We highlight the similarities and differences in the impact on four major CNS diseases, i.e., multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, and autism spectrum disorder, to identify common cellular and molecular networks governing the regulation of cellular constituents and pathogenesis in the CNS by microbial metabolites.

scholarly journals Hearing Loss in Neurological Disorders

2021 ◽  
Vol 9 ◽  
Author(s):  
Siyu Li ◽  
Cheng Cheng ◽  
Ling Lu ◽  
Xiaofeng Ma ◽  
Xiaoli Zhang ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hair Cells ◽  
Neurological Disorders ◽  
Molecular Mechanisms ◽  
Relevant Literature ◽  
Autism Spectrum ◽  
Supporting Cells ◽  
Cochlear Hair Cells ◽  
Wide Range ◽  
Histological Characteristics

Sensorineural hearing loss (SNHL) affects approximately 466 million people worldwide, which is projected to reach 900 million by 2050. Its histological characteristics are lesions in cochlear hair cells, supporting cells, and auditory nerve endings. Neurological disorders cover a wide range of diseases affecting the nervous system, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), autism spectrum disorder (ASD), etc. Many studies have revealed that neurological disorders manifest with hearing loss, in addition to typical nervous symptoms. The prevalence, manifestations, and neuropathological mechanisms underlying vary among different diseases. In this review, we discuss the relevant literature, from clinical trials to research mice models, to provide an overview of auditory dysfunctions in the most common neurological disorders, particularly those associated with hearing loss, and to explain their underlying pathological and molecular mechanisms.

The anticancer effects of curcumin via targeting the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway

2020 ◽  
Vol 156 ◽  
pp. 104798 ◽  
Author(s):  
Ahmad Tamaddoni ◽  
Elahe Mohammadi ◽  
Fatemeh Sedaghat ◽  
Durdi Qujeq ◽  
Atefeh As’Habi
Keyword(s):  
Signaling Pathway ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Anticancer Effects ◽  
Mtorc1 Signaling

scholarly journals mTOR Signaling Pathway Regulates Sperm Quality in Older Men

Cells ◽  
2019 ◽  
Vol 8 (6) ◽  
pp. 629 ◽  
Author(s):  
Silva ◽  
Cabral ◽  
Correia ◽  
Carvalho ◽  
Sousa ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Sperm Quality ◽  
Older Men ◽  
Mtor Signaling ◽  
Paternal Age ◽  
Signaling Proteins ◽  
Mtor Signaling Pathway ◽  
Mtorc1 Signaling ◽  
The Impact

: Understanding how age affects fertility becomes increasingly relevant as couples delay childbearing toward later stages of their lives. While the influence of maternal age on fertility is well established, the impact of paternal age is poorly characterized. Thus, this study aimed to understand the molecular mechanisms responsible for age-dependent decline in spermatozoa quality. To attain it, we evaluated the impact of male age on the activity of signaling proteins in two distinct spermatozoa populations: total spermatozoa fraction and highly motile/viable fraction. In older men, we observed an inhibition of the mechanistic target of rapamycin complex 1 (mTORC1) in the highly viable spermatozoa population. On the contrary, when considering the entire spermatozoa population (including defective/immotile/apoptotic cells) our findings support an active mTORC1 signaling pathway in older men. Additionally, total spermatozoa fractions of older men presented increased levels of apoptotic/stress markers (e.g., cellular tumor antigen p53-TP53) and mitogen-activated protein kinases (MAPKs) activity. Moreover, we established that the levels of most signaling proteins analyzed were consistently and significantly altered in men more than 27 years of age. This study was the first to associate the mTOR signaling pathway with the age impact on spermatozoa quality. Additionally, we constructed a network of the sperm proteins associated with male aging, identifying TP53 as a central player in spermatozoa aging.

scholarly journals Targeting the mTOR Signaling Pathway Utilizing Nanoparticles: A Critical Overview

Cancers ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. 82 ◽  
Author(s):  
Mariia Lunova ◽  
Barbora Smolková ◽  
Anna Lynnyk ◽  
Mariia Uzhytchak ◽  
Milan Jirsa ◽  
...  
Keyword(s):  
Structural Changes ◽  
Molecular Mechanisms ◽  
Therapeutic Option ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Signaling ◽  
Therapeutic Effects ◽  
Mtorc1 Signaling ◽  
Challenges And Opportunities ◽  
Signaling Axis ◽  
Mtor Modulation

Proteins of the mammalian target of rapamycin (mTOR) signaling axis are overexpressed or mutated in cancers. However, clinical inhibition of mTOR signaling as a therapeutic strategy in oncology shows rather limited progress. Nanoparticle-based mTOR targeted therapy proposes an attractive therapeutic option for various types of cancers. Along with the progress in the biomedical applications of nanoparticles, we start to realize the challenges and opportunities that lie ahead. Here, we critically analyze the current literature on the modulation of mTOR activity by nanoparticles, demonstrate the complexity of cellular responses to functionalized nanoparticles, and underline challenges lying in the identification of the molecular mechanisms of mTOR signaling affected by nanoparticles. We propose the idea that subcytotoxic doses of nanoparticles could be relevant for the induction of subcellular structural changes with possible involvement of mTORC1 signaling. The evaluation of the mechanisms and therapeutic effects of nanoparticle-based mTOR modulation will provide fundamental knowledge which could help in developing safe and efficient nano-therapeutics.

scholarly journals Manipulations of MeCP2 in glutamatergic neurons highlight their contributions to Rett and other neurological disorders

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Xiangling Meng ◽  
Wei Wang ◽  
Hui Lu ◽  
Ling-jie He ◽  
Wu Chen ◽  
...  
Keyword(s):  
Mouse Models ◽  
Neurological Disorders ◽  
Acoustic Startle ◽  
Acoustic Startle Response ◽  
Autism Spectrum ◽  
Inhibitory Neurons ◽  
Loss Of Function ◽  
Glutamatergic Neurons ◽  
Excitatory Neurotransmission ◽  
Spectrum Disorders

Many postnatal onset neurological disorders such as autism spectrum disorders (ASDs) and intellectual disability are thought to arise largely from disruption of excitatory/inhibitory homeostasis. Although mouse models of Rett syndrome (RTT), a postnatal neurological disorder caused by loss-of-function mutations in MECP2, display impaired excitatory neurotransmission, the RTT phenotype can be largely reproduced in mice simply by removing MeCP2 from inhibitory GABAergic neurons. To determine what role excitatory signaling impairment might play in RTT pathogenesis, we generated conditional mouse models with Mecp2 either removed from or expressed solely in glutamatergic neurons. MeCP2 deficiency in glutamatergic neurons leads to early lethality, obesity, tremor, altered anxiety-like behaviors, and impaired acoustic startle response, which is distinct from the phenotype of mice lacking MeCP2 only in inhibitory neurons. These findings reveal a role for excitatory signaling impairment in specific neurobehavioral abnormalities shared by RTT and other postnatal neurological disorders.

scholarly journals Complete Purging of Ewing Sarcoma Metastases from Human Ovarian Cortex Tissue Fragments by Inhibiting the mTORC1 Signaling Pathway

2021 ◽  
Vol 10 (19) ◽  
pp. 4362
Author(s):  
Ronald Peek ◽  
Lotte L. Eijkenboom ◽  
Didi D. M. Braat ◽  
Catharina C. M. Beerendonk
Keyword(s):  
Signaling Pathway ◽  
Ex Vivo ◽  
Ovarian Tissue ◽  
Autologous Transplantation ◽  
Mammalian Target Of Rapamycin ◽  
Short Term ◽  
Ovarian Cortex ◽  
Short Term Exposure ◽  
Mtorc1 Signaling ◽  
Restoration Of Fertility

Restoration of fertility by autologous transplantation of ovarian cortex tissue in former cancer patients may lead to the reintroduction of malignancy via the graft. Pharmacological ex vivo purging of ovarian cortex fragments prior to autotransplantation may reduce the risk of reseeding the cancer. In this study we have investigated the capacity of Everolimus (EVE), an inhibitor of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, to eradicate Ewing’s sarcoma (ES) from ovarian tissue by a short-term ex vivo treatment. Exposure of experimentally induced ES tumor foci in ovarian tissue to EVE for 24 h completely eliminated the malignant cells without detrimental effects on follicle morphology, survival or early folliculogenesis. This indicates that effective purging of ovarian cortex tissue from contaminating ES tumor foci is possible by short-term exposure to EVE.

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