Regulation of autophagy by mTOR-dependent and mTOR-independent pathways: autophagy dysfunction in neurodegenerative diseases and therapeutic application of autophagy enhancers.
TL;DR: The present review describes the cellular signalling pathways regulating mammalian autophagy and highlights the potential therapeutic application of Autophagy inducers in neurodegenerative disorders.
Abstract: Autophagy is an intracellular degradation pathway essential for cellular and energy homoeostasis It functions in the clearance of misfolded proteins and damaged organelles, as well as recycling of cytosolic components during starvation to compensate for nutrient deprivation This process is regulated by mTOR (mammalian target of rapamycin)-dependent and mTOR-independent pathways that are amenable to chemical perturbations Several small molecules modulating autophagy have been identified that have potential therapeutic application in diverse human diseases, including neurodegeneration Neurodegeneration-associated aggregation-prone proteins are predominantly degraded by autophagy and therefore stimulating this process with chemical inducers is beneficial in a wide range of transgenic disease models Emerging evidence indicates that compromised autophagy contributes to the aetiology of various neurodegenerative diseases related to protein conformational disorders by causing the accumulation of mutant proteins and cellular toxicity Combining the knowledge of autophagy dysfunction and the mechanism of drug action may thus be rational for designing targeted therapy The present review describes the cellular signalling pathways regulating mammalian autophagy and highlights the potential therapeutic application of autophagy inducers in neurodegenerative disorders
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TL;DR: The biological functions of autophagy genes are discussed from the perspective of understanding-and potentially reversing-the pathophysiology of human disease and aging.
1,432 citations
Cites background from "Regulation of autophagy by mTOR-dep..."
...There has been some interest in usingUS Food andDrug Administration [FDA]-approved mTOR inhibitors for the treatment of neurodegenerative disorders that may benefit from autophagy induction (Sarkar, 2013)....
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University of Graz1, Joanneum Research2, Research Institute of Molecular Pathology3, Institute of Molecular Biotechnology4, University of Natural Resources and Life Sciences, Vienna5, Foundation for Research & Technology – Hellas6, Austrian Academy of Sciences7, University of Salzburg8, University of Basel9, University of St Andrews10
TL;DR: Administration of spermidine markedly extended the lifespan of yeast, flies and worms, and human immune cells and inhibited oxidative stress in ageing mice, and found that enhanced autophagy is crucial for polyamine-induced suppression of necrosis and enhanced longevity.
Abstract: Ageing results from complex genetically and epigenetically programmed processes that are elicited in part by noxious or stressful events that cause programmed cell death Here, we report that administration of spermidine, a natural polyamine whose intracellular concentration declines during human ageing, markedly extended the lifespan of yeast, flies and worms, and human immune cells In addition, spermidine administration potently inhibited oxidative stress in ageing mice In ageing yeast, spermidine treatment triggered epigenetic deacetylation of histone H3 through inhibition of histone acetyltransferases (HAT), suppressing oxidative stress and necrosis Conversely, depletion of endogenous polyamines led to hyperacetylation, generation of reactive oxygen species, early necrotic death and decreased lifespan The altered acetylation status of the chromatin led to significant upregulation of various autophagy-related transcripts, triggering autophagy in yeast, flies, worms and human cells Finally, we found that enhanced autophagy is crucial for polyamine-induced suppression of necrosis and enhanced longevity
974 citations
TL;DR: The GFP- LC3-RFP-LC3ΔG probe is a simple and quantitative method to evaluate autophagic flux in cultured cells and whole organisms, and re-evaluated previously reported autophagy-modulating compounds, performed a high-throughput screen of an approved drug library, and identified autophile modulators.
363 citations
Cites background from "Regulation of autophagy by mTOR-dep..."
...Althoughseveral othergroupshaveperformedhigh-throughput screening using previously available probes (summarized in Sarkar, 2013; Vakifahmetoglu-Norberg et al., 2015; Levine et al., 2015), we were able to identify 13 novel inducers and 18 novel inhibitors in addition to previously known modulators....
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TL;DR: This commentary/review advances the premise that autophagy is actually populated by at least two additional players, and is now term the cytostatic form of autophagic in that its activation results in prolonged growth inhibition as well as reduced clonogenic survival but in the absence of actual loss of cell viability through apoptosis or necrosis.
Abstract: It is generally thought that autophagy has two primary and opposing functions in tumor cells in response to stress induced by chemotherapy or radiation. One is the cytoprotective function that can in theory be inhibited for therapeutic advantage by sensitizing the cells to these treatment modalities. The other is the cytotoxic function that is generally not observed with conventional treatment modalities, but that may function to promote tumor cell killing either alone or in association with apoptosis. In this commentary/review, we advance the premise that autophagy is actually populated by at least two additional players. One we have termed the nonprotective form of autophagy, where the cell is apparently carrying out autophagy-mediated degradative functions, but where autophagy inhibition does not lead to perceptible alterations in drug or radiation sensitivity. The other is what we now term the cytostatic form of autophagy in that its activation results in prolonged growth inhibition as well as reduced clonogenic survival (loss of reproductive capacity) but in the absence of actual loss of cell viability through apoptosis or necrosis; however, as is the case with cytototoxic autophagy, inhibition of cytostatic autophagy protects the tumor cell from the agent (drugs or radiation) that promotes the autophagic response. In view of current clinical efforts to exploit autophagy inhibition as a therapeutic strategy for sensitization of malignancies to chemotherapy and radiation, it is critical to recognize that if chemotherapy and/or radiation actually promote autophagy in patient tumors, the autophagy is not of necessity cytoprotective in function.
355 citations
Cites background from "Regulation of autophagy by mTOR-dep..."
...Given that a number of neurodegenerative diseases are characterized by defective autophagy (4), it is reasonable to assume that autophagy inhibition could prove to be quite detrimental to normal tissue....
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...marker for detecting autophagy induction in patients' tumors and certainly noway to distinguish between the different forms of autophagy; (iv) given their known pharmacokinetics, it is highly uncertain as to whether chloroquine or hydroxychloroquine can actually achieve concentrations in the tumor cells that will effectively inhibit autophagy; in fact, we are inclined to argue that the reason that chloroquine and hydroxychloroquine have proven to be relatively nontoxic to patients is because of the fact that they do not actually suppress autophagy at concentrations that are achieved in normal clinical regimens; and (v) because it has been shown that deficiencies in autophagy are associated with human disease (4), any drug that actually is found to suppress autophagy in tumor cells is likely to be quite detrimental to normal tissue homeostasis because autophagy is clearly necessary for the routine elimination of damaged or misfunctional proteins....
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TL;DR: It is clear that mTOR and autophagy are closely integrated within cells, where defects in signalling through both pathways are known to drive the onset of a range of human diseases, such as cancer and neurodegenerative disease.
351 citations
References
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TL;DR: Tight genetic linkage between FALS and a gene that encodes a cytosolic, Cu/Zn-binding superoxide dismutase (SOD1), a homodimeric metalloenzyme that catalyzes the dismutation of the toxic superoxide anion O–2 to O2 and H2O2 is reported.
Abstract: Amyotrophic lateral sclerosis (ALS) is a degenerative disorder of motor neurons in the cortex, brainstem and spinal cord. Its cause is unknown and it is uniformly fatal, typically within five years. About 10% of cases are inherited as an autosomal dominant trait, with high penetrance after the sixth decade. In most instances, sporadic and autosomal dominant familial ALS (FALS) are clinically similar. We have previously shown that in some but not all FALS pedigrees the disease is linked to a genetic defect on chromosome 21q (refs 8, 9). Here we report tight genetic linkage between FALS and a gene that encodes a cytosolic, Cu/Zn-binding superoxide dismutase (SOD1), a homodimeric metalloenzyme that catalyzes the dismutation of the toxic superoxide anion O2.- to O2 and H2O2 (ref. 10). Given this linkage and the potential role of free radical toxicity in other neurodenegerative disorders, we investigated SOD1 as a candidate gene in FALS. We identified 11 different SOD1 missense mutations in 13 different FALS families.
6,733 citations
TL;DR: It is demonstrated that Akt also regulates the activity of FKHRL1, a member of the Forkhead family of transcription factors, which triggers apoptosis most likely by inducing the expression of genes that are critical for cell death, such as the Fas ligand gene.
6,481 citations
TL;DR: Inositol trisphosphate is a second messenger that controls many cellular processes by generating internal calcium signals through receptors whose molecular and physiological properties closely resemble the calcium-mobilizing ryanodine receptors of muscle.
Abstract: Inositol trisphosphate is a second messenger that controls many cellular processes by generating internal calcium signals. It operates through receptors whose molecular and physiological properties closely resemble the calcium-mobilizing ryanodine receptors of muscle. This family of intracellular calcium channels displays the regenerative process of calcium-induced calcium release responsible for the complex spatiotemporal patterns of calcium waves and oscillations. Such a dynamic signalling pathway controls many cellular processes, including fertilization, cell growth, transformation, secretion, smooth muscle contraction, sensory perception and neuronal signalling.
6,389 citations
01 Apr 2012
TL;DR: The mechanistic target of rapamycin (mTOR) signaling pathway senses and integrates a variety of environmental cues to regulate organismal growth and homeostasis as mentioned in this paper, and is implicated in an increasing number of pathological conditions, including cancer, obesity, type 2 diabetes, and neurodegeneration.
Abstract: The mechanistic target of rapamycin (mTOR) signaling pathway senses and integrates a variety of environmental cues to regulate organismal growth and homeostasis. The pathway regulates many major cellular processes and is implicated in an increasing number of pathological conditions, including cancer, obesity, type 2 diabetes, and neurodegeneration. Here, we review recent advances in our understanding of the mTOR pathway and its role in health, disease, and aging. We further discuss pharmacological approaches to treat human pathologies linked to mTOR deregulation.
6,268 citations
TL;DR: It is demonstrated that the rat microtubule‐associated protein 1 light chain 3 (LC3), a homologue of Apg8p essential for autophagy in yeast, is associated to the autophagosome membranes after processing.
Abstract: Little is known about the protein constituents of autophagosome membranes in mammalian cells. Here we demonstrate that the rat microtubule-associated protein 1 light chain 3 (LC3), a homologue of Apg8p essential for autophagy in yeast, is associated to the autophagosome membranes after processing. Two forms of LC3, called LC3-I and -II, were produced post-translationally in various cells. LC3-I is cytosolic, whereas LC3-II is membrane bound. The autophagic vacuole fraction prepared from starved rat liver was enriched with LC3-II. Immunoelectron microscopy on LC3 revealed specific labelling of autophagosome membranes in addition to the cytoplasmic labelling. LC3-II was present both inside and outside of autophagosomes. Mutational analyses suggest that LC3-I is formed by the removal of the C-terminal 22 amino acids from newly synthesized LC3, followed by the conversion of a fraction of LC3-I into LC3-II. The amount of LC3-II is correlated with the extent of autophagosome formation. LC3-II is the first mammalian protein identified that specifically associates with autophagosome membranes.
6,244 citations