mTOR-Dependent Cell Proliferation in the Brain

Ryskalin, Larisa; Lazzeri, Gloria; Flaibani, Marina; Biagioni, Francesca; Gambardella, Stefano; Frati, Alessandro; Fornai, Francesco

doi:10.1155/2017/7082696

Cited by 74 publications

(67 citation statements)

References 200 publications

(223 reference statements)

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“…Surprisingly, we find that cortical excitatory neurons in fact show an opposite downregulation trend for both types of processes, indicating that they respond to the loss of FMRP differently than inhibitory neurons and possibly are reflecting a decrease in mTOR activity. Indeed, stimulation of the N-methyl-D-aspartate receptor (NMDAR) decreases mTOR signaling activity [96][97][98] . We find that NMDAR subunits are most highly expressed in excitatory neurons ( Figure S4a).…”

Section: Discussionmentioning

confidence: 99%

Single Cell Transcriptomics Reveals Dysregulated Cellular and Molecular Networks in a Fragile X Syndrome model

Donnard

Shu

Garber

2020

Preprint

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Despite advances in understanding the pathophysiology of Fragile X syndrome (FXS), its molecular bases are still poorly understood. Whole brain tissue expression profiles have proved surprisingly uninformative. We applied single cell RNA sequencing to profile a FXS mouse model. We found that FXS results in a highly cell type specific effect and it is strongest among different neuronal types. We detected a downregulation of mRNAs bound by FMRP and this effect is prominent in neurons. Metabolic pathways including translation are significantly upregulated across all cell types with the notable exception of excitatory neurons. These effects point to a potential difference in the activity of mTOR pathways, and together with other dysregulated pathways suggest an excitatory-inhibitory imbalance in the FXS cortex which is exacerbated by astrocytes. Our data demonstrate the cell-type specific complexity of FXS and provide a resource for interrogating the biological basis of this disorder.

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Section: Discussionmentioning

confidence: 99%

Single Cell Transcriptomics Reveals Dysregulated Cellular and Molecular Networks in a Fragile X Syndrome model

Donnard

Shu

Garber

2020

Preprint

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“…In fact, mice deficient for autophagy-related proteins, such as Atg5 or Atg7, show inclusion bodies and marked neuronal loss [43,44]. In line with this, mTOR-dependent impairment of autophagy is implicated in various neuropsychiatric disorders such as dementia, movement disorders, motor neuron disease, seizures, brain ischemia, autism, affective disorders, addiction, and schizophrenia [45,46,47,48,49,50,51,52,53,54,55,56,57]. While the involvement of autophagy in neurological disorders is intensely investigated, the evidence about an involvement of autophagy in psychiatric disorders is less clear.…”

Section: Introductionmentioning

confidence: 97%

mTOR-Related Brain Dysfunctions in Neuropsychiatric Disorders

Ryskalin

Limanaqi

Frati

et al. 2018

IJMS

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The mammalian target of rapamycin (mTOR) is an ubiquitously expressed serine-threonine kinase, which senses and integrates several intracellular and environmental cues to orchestrate major processes such as cell growth and metabolism. Altered mTOR signalling is associated with brain malformation and neurological disorders. Emerging evidence indicates that even subtle defects in the mTOR pathway may produce severe effects, which are evident as neurological and psychiatric disorders. On the other hand, administration of mTOR inhibitors may be beneficial for a variety of neuropsychiatric alterations encompassing neurodegeneration, brain tumors, brain ischemia, epilepsy, autism, mood disorders, drugs of abuse, and schizophrenia. mTOR has been widely implicated in synaptic plasticity and autophagy activation. This review addresses the role of mTOR-dependent autophagy dysfunction in a variety of neuropsychiatric disorders, to focus mainly on psychiatric syndromes including schizophrenia and drug addiction. For instance, amphetamines-induced addiction fairly overlaps with some neuropsychiatric disorders including neurodegeneration and schizophrenia. For this reason, in the present review, a special emphasis is placed on the role of mTOR on methamphetamine-induced brain alterations.

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“…It is noteworthy that MTOR expression is normally increasingly inhibited in the ageing brain [298,299], and hence the existence of elevated mTOR activity in the hippocampus of AD patients could be a factor underpinning dysfunctional autophagic lysosomal clearance in that region of the brain, as discussed above. From the wider perspective of AD pathology, mTOR has several roles, such as the regulation of many aspects of synaptic function and protein aggregation, and is known to promote ptau and tau dyshomeostasis [300][301][302][303].…”

Section: Oxidative Stress Mtor Activation and Impaired Autophagy And mentioning

confidence: 97%

Could Alzheimer’s Disease Originate in the Periphery and If So How So?

et al. 2018

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The classical amyloid cascade model for Alzheimer's disease (AD) has been challenged by several findings. Here, an alternative molecular neurobiological model is proposed. It is shown that the presence of the APOE ε4 allele, altered miRNA expression and epigenetic dysregulation in the promoter region and exon 1 of TREM2, as well as ANK1 hypermethylation and altered levels of histone post-translational methylation leading to increased transcription of TNFA, could variously explain increased levels of peripheral and central inflammation found in AD. In particular, as a result of increased activity of triggering receptor expressed on myeloid cells 2 (TREM-2), the presence of the apolipoprotein E4 (ApoE4) isoform, and changes in ANK1 expression, with subsequent changes in miR-486 leading to altered levels of protein kinase B (Akt), mechanistic (previously mammalian) target of rapamycin (mTOR) and signal transducer and activator of transcription 3 (STAT3), all of which play major roles in microglial activation, proliferation and survival, there is activation of microglia, leading to the subsequent (further) production of cytokines, chemokines, nitric oxide, prostaglandins, reactive oxygen species, inducible nitric oxide synthase and cyclooxygenase-2, and other mediators of inflammation and neurotoxicity. These changes are associated with the development of amyloid and tau pathology, mitochondrial dysfunction (including impaired activity of the electron transport chain, depleted basal mitochondrial potential and oxidative damage to key tricarboxylic acid enzymes), synaptic dysfunction, altered glycogen synthase kinase-3 (GSK-3) activity, mTOR activation, impairment of autophagy, compromised ubiquitin-proteasome system, iron dyshomeostasis, changes in APP translation, amyloid plaque formation, tau hyperphosphorylation and neurofibrillary tangle formation.

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mTOR-Dependent Cell Proliferation in the Brain

Cited by 74 publications

References 200 publications

Single Cell Transcriptomics Reveals Dysregulated Cellular and Molecular Networks in a Fragile X Syndrome model

Single Cell Transcriptomics Reveals Dysregulated Cellular and Molecular Networks in a Fragile X Syndrome model

mTOR-Related Brain Dysfunctions in Neuropsychiatric Disorders

Could Alzheimer’s Disease Originate in the Periphery and If So How So?

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