Novel compounds for the modulation of mTOR and autophagy to treat neurodegenerative diseases

Heras-Sandoval, David; Pérez‐Rojas, Jazmin M.; Pedraza‐Chaverrí, José

doi:10.1016/j.cellsig.2019.109442

Cited by 60 publications

(40 citation statements)

References 95 publications

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“…Apelin expression has been described in endothelial cells and the CNS [82] and has also been found to be involved in neuronal dysfunction related to inflammation during ageing [83]. Modulation of apelin signalling has been discussed in a range of pathologies [84] and has recently also been associated with neurodegenerative diseases [85], including AD [86][87][88][89] and PD [90][91][92]. However, specific roles in PD remain to be further investigated.…”

Section: Discussionmentioning

confidence: 99%

Protein Deimination Signatures in Plasma and Plasma-EVs and Protein Deimination in the Brain Vasculature in a Rat Model of Pre-Motor Parkinson’s Disease

Sancandi¹,

Uysal-Onganer

Kraev

et al. 2020

IJMS

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The identification of biomarkers for early diagnosis of Parkinson's disease (PD) is of pivotal importance for improving approaches for clinical intervention. The use of translatable animal models of pre-motor PD therefore offers optimal opportunities for novel biomarker discovery in vivo. Peptidylarginine deiminases (PADs) are a family of calcium-activated enzymes that contribute to protein misfolding through post-translational deimination of arginine to citrulline. Furthermore, PADs are an active regulator of extracellular vesicle (EV) release. Both protein deimination and extracellular vesicles (EVs) are gaining increased attention in relation to neurodegenerative diseases, including in PD, while roles in pre-motor PD have yet to be investigated. The current study aimed at identifying protein candidates of deimination in plasma and plasma-EVs in a rat model of pre-motor PD, to assess putative contributions of such post-translational changes in the early stages of disease. EV-cargo was further assessed for deiminated proteins as well as three key micro-RNAs known to contribute to inflammation and hypoxia (miR21, miR155, and miR210) and also associated with PD. Overall, there was a significant increase in circulating plasma EVs in the PD model compared with sham animals and inflammatory and hypoxia related microRNAs were significantly increased in plasma-EVs of the pre-motor PD model. A significantly higher number of protein candidates were deiminated in the pre-motor PD model plasma and plasma-EVs, compared with those in the sham animals. KEGG (Kyoto encyclopedia of genes and genomes) pathways identified for deiminated proteins in the pre-motor PD model were linked to "Alzheimer's disease", "PD", "Huntington's disease", "prion diseases", as well as for "oxidative phosphorylation", "thermogenesis", "metabolic pathways", "Staphylococcus aureus infection", gap junction, "platelet activation", "apelin signalling", "retrograde endocannabinoid signalling", "systemic lupus erythematosus", and "non-alcoholic fatty liver disease". Furthermore, PD brains showed significantly increased staining for total deiminated proteins in the brain vasculature in cortex and hippocampus, as well as increased immunodetection of deiminated histone H3 in dentate gyrus and cortex. Our findings identify EVs and post-translational protein deimination as novel biomarkers in early pre-motor stages of PD. Figure 2. EV characterisation from rat plasma. (A) Representative Nanosight graphs showing nanoparticle tracking analysis (NTA) analysis of plasma EV profiles from sham-treated rats (Sham; n = 3). (B) Representative Nanosight graphs showing NTA analysis of plasma EV profiles from the premotor PD rat models (PD; n = 3). (C) Western blotting (WB) confirms that rat plasma-EVs are positive for the EV-specific markers CD63 and flotillin-1 (Flot-1); the molecular weight standard is indicated in kilo Daltons (kDa). (D,E) Transmission electron microscopy (TEM) images showing EVs isolated from sham (D) and pre-motor PD model (PD; (E)) rat plasma, revea...

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Section: Discussionmentioning

confidence: 99%

Protein Deimination Signatures in Plasma and Plasma-EVs and Protein Deimination in the Brain Vasculature in a Rat Model of Pre-Motor Parkinson’s Disease

Sancandi¹,

Uysal-Onganer

Kraev

et al. 2020

IJMS

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“…Mammalian target of rapamycin (mTOR) is a relatively conservative protein kinase of the phosphatidylinositol 3-kinase (PtdIns3K)-related family. Many studies have suggested a leading status for mTOR in autophagy [53,59,60]. Phosphatidylinositide 3-kinases (PI3K) and serine/threonine kinase (Akt) are upstream of mTOR, which could lead to the deactivation of mTOR by phosphorylation and trigger autophagy.…”

Section: Discussionmentioning

confidence: 99%

The interrupted effect of autophagic flux and lysosomal function induced by graphene oxide in p62-dependent apoptosis of F98 cells

Zhang

Feng

et al. 2020

J Nanobiotechnol

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Background: Graphene oxide (GO) nanoparticles (NPs) have been widely applied in various fields, especially in biomedical applications. Extensive studies have suggested that GO can pass through the blood-brain barrier (BBB) and induce abnormal autophagy and cytotoxicity in the central nervous system (CNS). However, the effect and specific mechanism of GO on astrocytes, the most abundant cells in the brain still has not been extensively investigated. Results: In this study, we systematically explored the toxicity and mechanism of GO exposure in the rat astrogliomaderived F98 cell line using molecular biological techniques (immunofluorescence staining, flow cytometry and Western blot) at the subcellular level and the signaling pathway level. Cells exposed to GO exhibited decreased cell viability and increased lactate dehydrogenase (LDH) release in a concentration-and time-dependent manner. GO-induced autophagy was evidenced by transmission electron microscopy (TEM) and immunofluorescence staining. Western blots showed that LC3II/I and p62 were upregulated and PI3K/Akt/mTOR was downregulated. Detection of lysosomal acidity and cathepsin B activity assay indicated the impairment of lysosomal function. Annexin V-FITC-PI detection showed the occurrence of apoptosis after GO exposure. The decrease in mitochondrial membrane potential (MMP) with an accompanying upregulation of cleaved caspase-3 and Bax/Bcl-2 further suggested that endogenous signaling pathways were involved in GO-induced apoptosis. Conclusion: The exposure of F98 cells to GO can elicit concentration-and time-dependent toxicological effects. Additionally, increased autophagic response can be triggered after GO treatment and that the blocking of autophagy flux plays a vital role in GO cytotoxicity, which was determined to be related to dysfunction of lysosomal degradation. Importantly, the abnormal accumulation of autophagic substrate p62 protein can induce capase-3-mediated apoptosis. Inhibition of abnormal accumulation of autophagic cargo could alleviate the occurrence of GO-induced apoptosis in F98 cells.

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“…Neurons are post-mitotic cells that are more prone to the accumulation of toxic metabolic byproducts than dividing cells, which experience higher regeneration of cytoplasm and organelles (Lee, 2012;Meng et al, 2019). Because of the high energy demands of the brain, neurons are sensitive to starvation, which is known to initiate autophagy through the mammalian target of rapamycin (mTOR) pathway (Heras-Sandoval et al, 2019). Conversely, inhibition of autophagy has been shown to cause neurodegeneration in mice (Komatsu et al, 2006) while knockout of autophagy genes in mice showed a range of neurodefective phenotypes; autophagy was also impaired in glial cells but the role of autophagy in glia and the effects of its impairment have not been explored sufficiently at this time to draw any conclusions (Nikoletopoulou et al, 2015).…”

Section: Apoptosismentioning

confidence: 99%

Molecular Pathogenicity of Enteroviruses Causing Neurological Disease

Majer¹,

McGreevy

Booth

2020

Front. Microbiol.

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Enteroviruses are single-stranded positive-sense RNA viruses that primarily cause self-limiting gastrointestinal or respiratory illness. In some cases, these viruses can invade the central nervous system, causing life-threatening neurological diseases including encephalitis, meningitis and acute flaccid paralysis (AFP). As we near the global eradication of poliovirus, formerly the major cause of AFP, the number of AFP cases have not diminished implying a non-poliovirus etiology. As the number of enteroviruses linked with neurological disease is expanding, of which many had previously little clinical significance, these viruses are becoming increasingly important to public health. Our current understanding of these non-polio enteroviruses is limited, especially with regards to their neurovirulence. Elucidating the molecular pathogenesis of these viruses is paramount for the development of effective therapeutic strategies. This review summarizes the clinical diseases associated with neurotropic enteroviruses and discusses recent advances in the understanding of viral invasion of the central nervous system, cell tropism and molecular pathogenesis as it correlates with host responses.

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Novel compounds for the modulation of mTOR and autophagy to treat neurodegenerative diseases

Cited by 60 publications

References 95 publications

Protein Deimination Signatures in Plasma and Plasma-EVs and Protein Deimination in the Brain Vasculature in a Rat Model of Pre-Motor Parkinson’s Disease

Protein Deimination Signatures in Plasma and Plasma-EVs and Protein Deimination in the Brain Vasculature in a Rat Model of Pre-Motor Parkinson’s Disease

The interrupted effect of autophagic flux and lysosomal function induced by graphene oxide in p62-dependent apoptosis of F98 cells

Molecular Pathogenicity of Enteroviruses Causing Neurological Disease

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