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Autophagy and autophagy enhancers

Autophagy and autophagy enhancers

Finally, Autophgay results were obtained Functional movement screening P-type ATPase ATP13A2 in the frontal cortex of PD and DLB patients, Autophagy and autophagy enhancers Ajtophagy both decreased [ 63 ] and increased [ 64 ] protein levels have been reported compared to controls. Lee: K2A2A; H. Tumorigenesis begins with an oncogene mutation in the epithelial cell that makes the cell more likely to divide.

Autophagy and autophagy enhancers -

One of these, sequestosome 1 SQSTM1 , encodes the scaffold protein p62; both point mutations and deletions have been identified in ALS cases 50 , p62 acts as an adaptor to bind ubiquitinated targets to autophagosome-associated lipidated microtubule—associated light chain 3 LC3-II for engulfment by autophagosomes While this suggests a clear link between autophagy and ALS, p62 mutations are located throughout the protein, across multiple domains 51 , and their effect on autophagy has yet to be fully established.

This is also true for ALS-causing mutations in another adaptor, optineurin Optineurin has established roles in xenophagy, a form of autophagy that degrades foreign pathogens Optineurin can also bind to protein aggregates 56 and is sequestered in inclusions in ALS patients as well as in other neurodegenerative diseases 57 , The most common known mutation in ALS is an intronic hexanucleotide repeat expansion in the gene C9ORF Very little is known about the function of the C9ORF72 protein, and it is currently unclear whether the disease resulting from this mutation is due to a loss of function, gain of function, or both.

siRNA knockdown of C9ORF72 increased LC3-II levels, although the study did not fully characterize the meaning of this in terms of autophagy function Yet another ALS-causing gene with a clear function in autophagy is dynactin 1 DCTN1 Autophagosomes are formed throughout neurons, and their efficient movement to lysosome-rich areas for fusion and cargo degradation is dependent on dynein-mediated transport 61 , A reduction in this transport can result in impaired autophagosome-lysosome fusion, as shown by autophagosome accumulation with enhanced toxicity in cell, Drosophila , and mouse models 63 , More recently, mutations in DCTN1 have been shown to cause Perry syndrome, a neurodegenerative disease that can present with Parkinsonism and psychiatric changes 65 , suggesting a role for autophagic dysfunction in this disease.

HD is caused by polyglutamine repeat expansions in the huntingtin htt protein A role for autophagy in HD was first suggested by observations of increased levels of autophagic markers in the brains or tissues of HD patients and in mouse models of the disease 67 — In HD mouse models, the key autophagic regulator, mTOR, is sequestered into htt aggregates, resulting in an inhibition of signaling, consistent with autophagy induction While this would appear to suggest an upregulation of autophagy in HD, the situation may in fact be more complicated.

The positive autophagy regulator, beclin 1, has also been shown to be sequestered into htt aggregates 71 , which would negatively affect autophagosome formation. Moreover, the accumulated autophagosomes observed may not be fully functional; they have been shown to be relatively empty due to inefficient sequestration of cargo, in particular organelles such as mitochondria and lipid droplets, and the increase in autophagosome number is not associated with an increase in protein degradation In addition, htt itself may control autophagy through a variety of different mechanisms.

Two htt-interacting proteins, Rab5 and Rhes, are positive regulators of autophagy 73 , 74 , and htt lacking the polyglutamine repeat region induces autophagy and is protective against toxicity of mutant polyglutamine—expanded htt in cells and mice 75 , suggesting a more direct role for htt in autophagy.

While it is not yet clear whether alterations in autophagy are primary factors in the pathogenesis of HD, polymorphisms in the core autophagy gene, ATG7 , have been suggested to be associated with earlier age of onset Hereditary spastic paraplegia.

Hereditary spastic paraplegias HSPs include a broad group of neurodegenerative diseases involving degeneration associated with the lower extremities.

Two forms of HSP have been associated with mutations in genes with a role in autophagy. The first identified was TECPR2 , a positive autophagy regulator that interacts with LC3 77 , The exact function of this protein is unknown; however, it bears homology to TECPR1, which has been implicated in sequestration of bacteria into autophagosomes, suggesting a role as an autophagy adaptor Type 15 HSP is caused by mutations in ZFYVE26 79 encoding spastizin also known as FYVE-CENT , which interacts with the core autophagy protein, beclin 1.

Disease-associated mutations in spastizin compromise this interaction, leading to impaired autophagy Lafora disease. Lafora disease is an autosomal recessive myoclonous epilepsy resulting in early death due to neurodegeneration.

Its pathologic hallmark is the accumulation of Lafora bodies LBs , comprising abnormally hyperphosphorylated polyglucosan with a smaller polyubiquitinated protein component.

Most mutations in Lafora disease occur in two proteins, laforin and malin, which form a complex that, when disrupted, drives the disease reviewed in ref. LB accumulation may be partly the result of altered carbohydrate metabolism However, data from patient and animal models clearly support a role for disrupted autophagy in disease onset and progression.

Overexpression of laforin induces autophagy, while a reduction in laforin levels has the opposite effect Both laforin- and malin-deficient mice show an early defect in autophagosome biogenesis, which may lead to LB formation 83 — Both mouse models show reduced levels of autophagosomes and a reduction in total and autophagy-dependent protein degradation.

Neurodegenerative disorders associated with mutations in core autophagy genes. The likelihood that autophagy defects contribute to neurodegeneration is supported by recent studies that reveal a class of diseases caused by mutations in core autophagy genes.

Neurodegeneration with brain iron accumulation 5 NBIA5; OMIM identifier is a neurodegenerative disease that presents with movement disorder and intellectual decline. It is currently described as β-propeller protein—associated neurodegeneration BPAN or static encephalopathy of childhood with neurodegeneration in adulthood SENDA BPAN appears to be a sporadic disease, with mutations in WIPI4 occurring de novo, as parents and siblings in 20 subjects did not share the mutations In lymphoblastoid cell lines from five patients, reduced autophagic activity and an accumulation of aberrant ATG9A and LC3-II positive autophagic structures were reported This may be a direct result of disrupted ATG9A vesicle translocation at the autophagosome formation site 88 due to altered WIPI4 activity in autophagosome formation 89 , Another disease caused by an autophagy gene defect is Vici syndrome OMIM identifier , a multisystem disorder associated with callosal agenesis.

This disorder is caused by recessive mutations in EPG5 , an autophagy gene identified first in Caenorhabditis elegans Epg5 -null mice develop ALS-like features The evidence outlined above suggests a possible role for autophagic dysfunction in the pathogenesis of neurodegenerative diseases, but autophagy also has the ability to decrease the accumulation of toxic, aggregate-prone proteins that cause neurodegeneration.

These aggregate-prone proteins are frequently substrates for both the ubiquitin-proteasome system and autophagy as monomers. However, because the oligomeric forms of these proteins cannot pass through the narrow entrance of the proteasome, such higher-order species may be targeted to autophagy.

While the appearance of intracytoplasmic inclusions is reduced by autophagy upregulation, our working model is that autophagy does not clear the large aggregates directly, but rather clears the soluble aggregate precursors, shifting the equilibrium from aggregate formation toward degradation Multiple studies provide proof of principle for the modulation of autophagy as a therapy for neurodegenerative disease.

In vitro work examining the effect of autophagy upregulation on the clearance of a wide range of aggregation-prone proteins including those with polyQ and polyA expansions 5 , 8 , mutant tau and ataxin-3 8 , and mutant α-synuclein 6 , 94 has suggested reductions in both intracytoplasmic aggregates and associated cell death.

Additionally, autophagy also protects against both proapoptotic 95 , 96 and pro-necrotic 97 insults, which may contribute to its benefits. The protective effect seen from autophagy induction in cell models has been successfully translated into a range of animal models, in Drosophila melanogaster models of both tauopathies 8 and HD 70 , 98 , and also in mammalian models of disease, including HD, spinocerebellar ataxia type III, tauopathy, PD, and even familial prion disease see Table 1 for studies of autophagy upregulation in mouse models of neurodegeneration.

Together these studies demonstrate that autophagy upregulation and promotion of aggregation-prone protein degradation ameliorate neurodegenerative pathology. Therapeutic upregulation of autophagy in transgenic mouse models of neurodegenerative disease. It is important to note that autophagy inducers are unlikely to be panaceas for all neurodegenerative diseases.

Indeed, in diseases associated with impaired autophagosome clearance e. A greater understanding of the potential mechanisms of autophagic dysfunction in neurodegenerative disease as outlined in the first part of this Review is therefore vital for development of therapeutics.

The autophagy-modulating agents used in preclinical trials in models of neurodegenerative disease have diverse mechanisms of action. Our understanding of how many of these agents work is not complete; however, they can be divided into mTOR-dependent and mTOR-independent agents.

mTOR-dependent pharmacologic agents. mTOR is found in two different functional complexes. mTOR complex 1 mTORC1 is a negative autophagy regulator, and mTORC2 is a positive regulator The allosteric mTORC1 inhibitor rapamycin was the first drug to be identified as an autophagy inducer , Rapamycin forms a complex with FKbinding protein 12 FKBP12 , which binds to and inhibits the kinase activity of mTORC1 , Although the mTOR pathway is involved in a wide range of cellular functions reviewed in ref.

The limited absorption of rapamycin has driven the development of many so-called rapalogs such as temsirolimus CCI , everolimus RAD , and ridaforolimus AP To date, it is these rapalogs that have been investigated most widely in terms of their potential therapeutic value in neurodegenerative diseases.

Newly developed mTOR inhibitors include the ATP-competitive mTOR inhibitors reviewed in ref. These results indicate the broad spectrum of biological activities of lithium and valproic acid, as suggest that a complex network of processes is involved in the pathogenesis of HD.

Valproic acid inhibits activity of myo-inositolphosphate synthase, one of enzymes involved in the metabolism of inositol Shaltiel et al. Combination of valproic acid and lithium was tested in clinical trials with HD patients. However, in most cases either a lack of effects or only stabilization of symptoms with no improvement were observed Scheuing et al.

AD model cells were treated with valproic acid, and no changes with the total amount of beta-amyloid were demonstrated while level of beta-amyloid oligomers which are suggested to be more toxic decreased and level of monomers increased, relative to untreated control cells Williams and Bate This may suggest that beta-amyloid oligomers are converted to monomers in valproic acid-treated cells.

Streptozotocin STZ -induced rat model of AD has been used in in vivo studies. Intraventricular injection of STZ provokes neurodegeneration and accumulation of beta-amyloid and hyperphosphorylated tau protein, thus, mimicking the sporadic form of AD. Decreased levels of acetylcholine and neprylysine, and increased activity of acetylcholinesterase cause additionally enhanced neurodegeneration and cognitive defects.

Treatment with valproic acid resulted in prevention of cognitive deficits and normalization of levels and activities of neurotransmitters Sorial and El Sayed Using another animal model of AD, transgenic mice expressing a mutated APP gene, effects of valproic acid in males and females were compared.

Decreased levels of amyloid plaques were more pronounced in males than in females, while number of synaptic vesicles were similar in both genders. On the other hand, neurodegeneration was prevented more efficiently in males Long et al.

Cellular models of PD were used to investigate the mechanism of action of valproic acid. This compound caused reduction of levels of proapoptotic proteins and ROS, while autophagy inhibitors diminished these effects, indicating a crucial role of this process in valproic acid-mediated improvement in PD cellular phenotypes Zhang et al.

Other in vitro studies were based on the use of murine neurons treated with human beta-amyloid. Defects in synaptic proteins and neurotransmitter transporting vesicles were observed. These effects were alleviated by addition of valproic acid into the cell culture. A mechanism has been proposed in which this compound negatively regulates cytoplasmic phospholipase A2 cPLAS2 , whose overactivity correlates with neurodegeneration.

Autophagy has been suggested as an additional mechanism of the observed changes in cells Williams and Bate Controversial results were obtained in studies on prion disease. Early studies suggested that valproic acid causes an increased accumulation of PrP in neuroblastoma cells and model cells for the disease.

However, administration of valproic acid to Chinese hamsters infected with prions did not cause any effects on the course of the disease Shaked et al. Other studies performed with cellular models did not confirm effects of valproic acid on the levels of PrP Legendre et al. Mechanism of action of carbamazepine is similar to that by valproic acid and lithium Williams et al.

A decrease in the inositol level arises from deprivation of PIP2 and IP3 Schiebler et al. Studies with the mouse model of AD indicated that carbamazepine improved learning abilities and memory, which was correlated with decreased number of amyloid plaques Li et al.

Apart from stimulation of mTOR-independent pathway of autophagy activation, carbamazepine inhibited the mTOR kinase activity. Therefore, it is another example of autophagy stimulation by more than one molecular mechanism Li et al. Since carbamazepine is known as an analgesic, anticonvulsant and antiepileptic drug, it has been used for treatment of HD patients Danivas et al.

It was proposed that its mechanisms of action is related to blocking calcium channels which cause inhibition of glutamate liberation Kawata et al. Intriguingly, autophagy was not considered as a mechanism by which carbamazepine improves symptoms of HD.

An interesting case report has been published in which carbamazepine was administered to a patient suffering from hypertension, myocardial infraction, and atrial fibrillation.

When high doses of the drug were used as the patient became resistant to lower doses , many adverse effects were noted, including memory deficits, confusion, psychomotor slowness, hypersomnia, dysphasia, and postural instability with falls.

Psychological tests indicated attentional deficits, perseverations, severe non-fluent aphasia with paraphasias, and constructional apraxia. The EEG results were similar to those found in patients suffering from Creutzfeldt—Jakob disease.

Cognitive deficit and motor dysfunctions normalized. Thus, it was concluded that carbamazepine caused Creutzfeldt—Jakob disease-like symptoms Horvath et al. Clonidine binds and activates the imidazoline receptor, which leads to a decrease in the level of cAMP in cells Williams et al.

However, it appears that there is an additional mechanism of action of this compound, namely activation of potassium channels which causes a decrease in concentration of calcium ions in the cytoplasm Murphy and Freedman Clonidine was used as one of compounds activating autophagy in the screening for a potential drug for HD and PD.

It was effective in reducing amounts of synuclein and mHTT in cells Williams et al. In vivo experiments were performed with reserpine-treated rat model of Parkinson's disease.

Following injection of reserpine, severe akinesis was observed which could be prevented by previous treatment with clonidine Hill and Brotchie However, stimulation of autophagy was not considered as a potential mechanism of action of this drug.

In PD potential therapies concentrate on inhibition of movements while patients suffer also from cognitive deficits and mood swings. When clonidine, as an agonist of adrenergic receptor alpha-2, was tested as a potential drug at early phase of PD in a monkey model Macaca fasicularis , it was found that the treatment caused improvement in concentration and memory Schneider et al.

Models of memory deficits were also used in studies on clonidine. In murine models, the symptoms were induced by administration of NMDA N-methyl-D-aspartate antagonist MK or by excitotoxic hippocampal damage. Clonidine ameliorated symptoms caused by MK, but did not change behavior of rats in which hippocampus was damaged by excitotoxic agents Bardgett et al.

The only studies on the use of clonidine in prion disease were performed with the yeast model. However, no significant effects on the level of PrPSC could be observed Tribouillard-Tanvier et al. Similarly to clonidine, it binds and activates the imidazoline receptor.

It was tested in experiments with cellular HD and PD models, and caused a decrease in levels of mHTT and alpha-synuclein Williams et al. In the mouse model of HD, reduction of mHTT levels was also observed but number of aggregates remained unchanged.

Although rilmenidine could not prevent the body weight loss, it corrected the muscle parameters and general condition of the organism Rose et al.

Although a clinical study with 18 HD patients has been conducted, only 12 patients completed this trial. Some cognitive parameters and motor functions were improved Underwood et al.

Cellular and animal models of ALS were used to study effects of rilmenidine in this disease. A decrease in mutant SOD1 level was observed in cells in which macroautophagy and mitophagy were also evident.

Similarly, administration of this drug to mice suffering from ALS resulted in autophagy induction in motor neurons. Unexpectedly, enhanced degeneration of these neurons was observed under these conditions.

Moreover, accumulation of SOD aggregates and a decrease in number of mitochondria occurred in treated animals, and correlated with more severe symptoms relative to untreated mice.

It was suggested that too extensive mitophagy could be responsible for these effects Perera et al. No reports were published on the use of this compound in experiments with animal models. When cellular model of AD was employed, treatment with SMER28 prevented formation of beta-amyloid aggregates in a dose-response mode Shen et al.

When production of Beclin-1 was impaired, effects of SMER28 were diminished. Similar effects were observed in experiments with silencing of expression of the gene coding for ULK kinase. Therefore, SMER28 appears to stimulate mTOR-dependent and mTOR-independent mechanisms of autophagy activation pathways Tian et al.

There are various possibilities to induce autophagy. In this review, mechanisms of these pathways were discussed to indicate how this process can be stimulated, which is in contrast to most other review article that described mechanisms of negative regulations in fact autophagy is regulated by various inhibitors.

Stimulation of autophagy has been considered as a strategy for treatment of various neurodegenerative diseases.

Although there are many encouraging results obtained in experiments with cellular and animal models described in this review in particular sections presenting various ways of autophagy stimulation , specific treatments of metabolic brain diseases are not yet available.

One of the most important problem is appearance of severe adverse effects when strong autophagy stimulators are tested. Such effects were observed for rapamycin, nimodipine, loperamide, niguldipine, nicardipine, panitrem A, fluspirilene, calpastatin, and carbamazepine.

Therefore, a compound which activates this process but is also safe in the long-term use is highly desirable.

In this light it is worth mentioning that genistein 5, 7-dihydroxy 4-hydroxyphenyl -4 H benzopyranone , a natural isoflavone, has been demonstrated recently to decrease levels of mutant huntingtin and to reduce number and size of aggregates of this toxic protein in the cellular model of HD by autophagy stimulation Pierzynowska et al.

This isoflavone could alleviate lysosomal storage of glycosaminoglycans in vitro and in vivo in visceral organs and in the brain , and correct animal behavior in various models of mucopolysaccharidosis type I, II and III, a neurodegenerative metabolic disease Piotrowska et al.

Therefore, it may be considered as a promising agent for development of an effective and safe therapeutics for treatment of neurodegenerative diseases by stimulation of autophagy. Interestingly, one compound is sometimes able to activate the autophagy process by both mTOR-dependent and mTOR-independent pathways.

Such molecules exemplified by L-NG-nitroarginine methyl ester, trehalose, pimozide or trifluoperazine are often very effective in removing toxic protein aggregates from cells. It is worth noting that there are links between different mTOR-dependent pathways, which may enhance effects of certain activators of autophagy.

Although no such links were discovered between mTOR-dependent and mTOR-independent pathways, the existence of compounds that stimulate autophagy by both these mechanisms might suggest a possibility that there are some cross-talks between molecules involved in both types of pathways.

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Immunity 27 , — Download references. The authors thank M. Jȁȁttelȁ for kind provision of p RLuc CA - LC3 WT and p RLuc CA - LC3 GA constructs and J.

Song for measurement of in vivo concentration of MSL or MSL Youle, E. Jho, A. Ballabio, L. Scorrano, T. Yoshimori, and H. Xu, respectively. M-S Lee and HJ Kwon are the recipient of UNIST Fund M3A9D to M-S Lee and NRF grants M. Lee: K2A2A; H. Kwon: K1A1A and M3A9C Severance Biomedical Science Institute, Seoul, Korea.

Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea. Department of Oral Biology, Yonsei University College of Dentistry, Seoul, Korea.

Global Research Laboratory, Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea. Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju, Korea. Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.

You can also search for this author in PubMed Google Scholar. and M. conceived the study. designed the experiments. conducted the experiments. wrote the manuscript with input from other authors. Correspondence to Myung-Shik Lee.

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Open Access This article is licensed under a Creative Commons Attribution 4. Reprints and permissions. Lim, H. A novel autophagy enhancer as a therapeutic agent against metabolic syndrome and diabetes. Nat Commun 9 , Download citation. Received : 22 March Accepted : 23 March Published : 12 April Anyone you share the following link with will be able to read this content:.

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Skip to main content Thank you for visiting nature. nature nature communications articles article. Download PDF. Subjects Macroautophagy Type 2 diabetes. Abstract Autophagy is a critical regulator of cellular homeostasis, dysregulation of which is associated with diverse diseases. Results Screening of autophagy enhancer small molecules To screen autophagy enhancers, we stably transfected HepG2 cells with wild-type WT p RLuc CA - LC3 or a mutant with GA substitution that is resistant to proteolytic cleavage and inhibits LC3-II formation [p RLuc CA - LC3 GA ] Full size image.

Discussion We here developed new potential therapeutics that can enhance autophagic activity and improve the metabolic profile of mice with metabolic syndrome and obesity. Cell death assay When treatment with chemicals was completed, medium was removed and 0.

Imaging and image quantification Imaging was conducted using an LSM confocal microscope Zeiss. Antibodies and Western blot analysis Cells or tissues were solubilized in a lysis buffer containing protease inhibitors. Mice experiments were not randomized and conducted without employing the blinding technique All animal experiments were conducted in accordance with the Public Health Service Policy in Humane Care and Use of Laboratory Animals.

NF-κB reporter assay NF-κB reporter activity was determined using pELAM-luciferase NF-κB reporter construct, as previously described Blood chemistry and hemogram Blood chemistry was determined using a Fuji Dri-Chem analyzer.

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Molecular Aitophagy volume 19Article Autophagy and autophagy enhancers 12 Cite this article. Metrics details. Autophagy, as a type II znd cell Autophagy and autophagy enhancers, Autopbagy crucial roles with Creative snack options ATG proteins in cancer. Ajtophagy plays a dynamic tumor-suppressive or tumor-promoting role in different contexts and stages of cancer development. In the early tumorigenesis, autophagy, as a survival pathway and quality-control mechanism, prevents tumor initiation and suppresses cancer progression. Once the tumors progress to late stage and are established and subjected to the environmental stresses, autophagy, as a dynamic degradation and recycling system, contributes to the survival and growth of the established tumors and promotes aggressiveness of the cancers by facilitating metastasis. Thank Autophagy and autophagy enhancers for visiting nature. You are enhances a browser version with snhancers support Autopyagy Citrus oil for hair. To obtain the best experience, we recommend Healthy metabolism catalyst use a more up to Autophavy browser or turn off compatibility aytophagy in Internet Enancers. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. We have reported that autophagy is crucial for clearance of amyloidogenic human IAPP hIAPP oligomer, suggesting that an autophagy enhancer could be a therapeutic modality against human diabetes with amyloid accumulation. Here, we show that a recently identified autophagy enhancer MSL-7 reduces hIAPP oligomer accumulation in human induced pluripotent stem cell-derived β-cells hiPSC-β-cells and diminishes oligomer-mediated apoptosis of β-cells. Autophagy and autophagy enhancers

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