bims-auttor Biomed news
on Autophagy and mTOR
Issue of 2019‒02‒24
seventeen papers selected by
Viktor Korolchuk
Newcastle University


  1. Adv Sci (Weinh). 2019 Feb 06. 6(3): 1801313
    Zou W, Lai M, Zhang Y, Zheng L, Xing Z, Li T, Zou Z, Song Q, Zhao X, Xia L, Yang J, Liu A, Zhang H, Cui ZK, Jiang Y, Bai X.
      Exosomes are small membrane-bound vesicles released into extracellular spaces by many types of cells. These nanovesicles carry proteins, mRNA, and miRNA, and are involved in cell waste management and intercellular communication. In the present study, it is shown that exosome release, which leads to net loss of cellular membrane and protein content, is negatively regulated by mechanistic target of rapamycin complex 1 (mTORC1). It is found that in cells and animal models exosome release is inhibited by sustained activation of mTORC1, leading to intracellular accumulation of CD63-positive exosome precursors. Inhibition of mTORC1 by rapamycin or nutrient and growth factor deprivation stimulates exosome release, which occurs concomitantly with autophagy. The drug-stimulated release is blocked by siRNA-mediated downregulation of small GTPase Rab27A. Analysis of the cargo content in exosomes released from rapamycin-treated cells reveals that inhibition of mTORC1 does not significantly alter its majority protein and miRNA profiles. These observations demonstrate that exosome release, like autophagy, is negatively regulated by mTORC1 in response to changes in nutrient and growth factor conditions.
    Keywords:  MVBs; TSC2; exosomes; mTORC1; rapamycin
    DOI:  https://doi.org/10.1002/advs.201801313
  2. Curr Genet. 2019 Feb 19.
    Gatica D, Klionsky DJ.
      In this report, we discuss recent discoveries concerning the effects and specificity of different RNA-binding proteins (RBPs) as they pertain to macroautophagy/autophagy. Autophagy is a fundamental cellular degradation and recycling pathway, which has attracted substantial attention because defects in this process are associated with a wide range of human disorders including cancer, neurodegeneration, and metabolic diseases. Autophagy must be tightly controlled-either too much or too little can be deleterious. Therefore, understanding the complex regulation of autophagy is critical to achieve the goal of modulating the process for therapeutic purposes. Autophagy occurs constitutively, but is upregulated in response to stress. Here, we highlight a role for various RBPs in regulating particular autophagy-related (ATG) mRNAs. We briefly summarize recent publications, which focus on the RBPs Dhh1, Pat1, Lsm1-Lsm7 and Dcp2 in the post-transcriptional regulation of certain mRNAs that encode key components of the autophagy machinery. Finally, we consider how the established role of these and other RBPs in enhancing decapping and downregulating mRNAs is not their only function when it comes to regulating stress-related transcripts. Most ATG genes are downregulated during growth, in contrast to the vast majority of the genome; we discuss how certain regulatory factors play a key role in maintaining autophagy at a basal level during growth, while allowing for a rapid increase when cells encounter various stress conditions.
    Keywords:  3′–5′ degradation; 5′–3′ degradation; Exosome; Lsm1; Mrt1; Xrn1; mRNA decay
    DOI:  https://doi.org/10.1007/s00294-019-00943-5
  3. Autophagy. 2019 Feb 20. 1-13
    McWilliams TG, Prescott AR, Villarejo-Zori B, Ball G, Boya P, Ganley IG.
      Photoreception is pivotal to our experience and perception of the natural world; hence the eye is of prime importance for most vertebrate animals to sense light. Central to visual health is mitochondrial homeostasis, and the selective autophagic turnover of mitochondria (mitophagy) is predicted to play a key role here. Despite studies that link aberrant mitophagy to ocular dysfunction, little is known about the prevalence of basal mitophagy, or its relationship to general autophagy, in the visual system. In this study, we utilize the mito-QC mouse and a closely related general macroautophagy reporter model to profile basal mitophagy and macroautophagy in the adult and developing eye. We report that ocular macroautophagy is widespread, but surprisingly mitophagy does not always follow the same pattern of occurrence. We observe low levels of mitophagy in the lens and ciliary body, in stark contrast to the high levels of general MAP1LC3-dependent macroautophagy in these regions. We uncover a striking reversal of this process in the adult retina, where mitophagy accounts for a larger degree of the macroautophagy taking place, specifically in the photoreceptor neurons of the outer nuclear layer. We also show the developmental regulation of autophagy in a variety of ocular tissues. In particular, mitophagy in the adult mouse retina is reversed in localization during the latter stages of development. Our work thus defines the landscape of mitochondrial homeostasis in the mammalian eye, and in doing so highlights the selective nature of autophagy in vivo and the specificity of the reporters used. Abbreviations: ATG: autophagy related; GFP: green fluorescent protein; LC3: microtubule associated protein 1 light chain 3; ONH: optic nerve head; ONL: outer nuclear layer; RPE: retinal pigment epithelium.
    Keywords:  -QC; Autophagy; ciliary body; cornea; eye; hyaloid; lens; mitochondria; mitophagy; retina
    DOI:  https://doi.org/10.1080/15548627.2019.1580509
  4. Int J Mol Sci. 2019 Feb 15. pii: E847. [Epub ahead of print]20(4):
    Chiarini F, Evangelisti C, Cenni V, Fazio A, Paganelli F, Martelli AM, Lattanzi G.
      The mechanistic target of rapamycin (mTOR) is a ubiquitous serine/threonine kinase that regulates anabolic and catabolic processes, in response to environmental inputs. The existence of mTOR in numerous cell compartments explains its specific ability to sense stress, execute growth signals, and regulate autophagy. mTOR signaling deregulation is closely related to aging and age-related disorders, among which progeroid laminopathies represent genetically characterized clinical entities with well-defined phenotypes. These diseases are caused by LMNA mutations and feature altered bone turnover, metabolic dysregulation, and mild to severe segmental progeria. Different LMNA mutations cause muscular, adipose tissue and nerve pathologies in the absence of major systemic involvement. This review explores recent advances on mTOR involvement in progeroid and tissue-specific laminopathies. Indeed, hyper-activation of protein kinase B (AKT)/mTOR signaling has been demonstrated in muscular laminopathies, and rescue of mTOR-regulated pathways increases lifespan in animal models of Emery-Dreifuss muscular dystrophy. Further, rapamycin, the best known mTOR inhibitor, has been used to elicit autophagy and degradation of mutated lamin A or progerin in progeroid cells. This review focuses on mTOR-dependent pathogenetic events identified in Emery-Dreifuss muscular dystrophy, LMNA-related cardiomyopathies, Hutchinson-Gilford Progeria, mandibuloacral dysplasia, and type 2 familial partial lipodystrophy. Pharmacological application of mTOR inhibitors in view of therapeutic strategies is also discussed.
    Keywords:  Emery-Dreifuss muscular dystrophy (EDMD); Hutchinson-Gilford progeria syndrome (HGPS); ageing; autophagy; bone remodeling; cellular signaling; lamin A/C; laminopathies; mTOR; metabolism
    DOI:  https://doi.org/10.3390/ijms20040847
  5. Curr Biol. 2019 Jan 30. pii: S0960-9822(19)30070-3. [Epub ahead of print]
    Chen Q, Xiao Y, Chai P, Zheng P, Teng J, Chen J.
      The endoplasmic reticulum (ER) consists of the nuclear envelope and both peripheral ER sheets and a peripheral tubular network [1, 2]. In response to physiological or pathological conditions, receptor-mediated selective ER-phagy, engulfing specific ER subdomains or components, is essential for ER turnover and homeostasis [3-6]. Four mammalian receptors for ER-phagy have been reported: FAM134B [7], reticulon 3 (RTN3) [8], SEC62 [9], and CCPG1 [10]. However, these ER-phagy receptors function in subcellular- and tissue- or physiological- and pathological-condition-specific manners, so the diversity of ER-phagy receptors and underlying mechanisms remain largely unknown [3, 4]. Atlastins (ATL1, ATL2, and ATL3), in mammals, are a class of membrane-bound, dynamin-like GTPases that function in ER fusion [11, 12]. ATL1 is expressed mainly in the central nervous system, while ATL2 and ATL3 are more ubiquitously distributed [13]. Recent studies showed that ATL2 mainly affects ER morphology by promoting ER fusion, whereas alterations in ER morphology are hardly detectable after ATL3 depletion [14, 15]. Here, we show that ATL3 functions as a receptor for ER-phagy, promoting tubular ER degradation upon starvation. ATL3 specifically binds to GABARAP, but not LC3, subfamily proteins via 2 GABARAP interaction motifs (GIMs). ATL3-GABARAP interaction is essential for ATL3 to function in ER-phagy. Moreover, hereditary sensory and autonomic neuropathy type I (HSAN I)-associated ATL3 mutations (Y192C and P338R) disrupt ATL3's association with GABARAP and impair ATL3's function in ER-phagy, suggesting that defective ER-phagy is involved in HSAN I. Therefore, we reveal a new ATL3 function for GABARAP-mediated ER-phagy in the degradation of tubular ER.
    Keywords:  ATL3; ER-phagy receptors; GABARAP; selective autophagy
    DOI:  https://doi.org/10.1016/j.cub.2019.01.041
  6. Exp Cell Res. 2019 Feb 15. pii: S0014-4827(19)30054-0. [Epub ahead of print]
    Danyu L, Yanran L, Xiuna J, Ying C, Sudan P, Tianen Z, Zhifen Z, Dezhi Z, Kaixun H, Yingyu X, Enxiang T.
      The transfer of misfolded α-Synuclein (α-Syn) from cell to cell as a prion protein is important in α-Synucleinopathies. Extraneous α-Syn induces apoptosis of dopaminergic neurons by causing mitochondrial dysfunction. However, the mechanism by which α-Syn disrupts the mitochondrial function is still unclear. In the present study, we used a gene microarray and western blotting analysis to show that the expression of mitochondrially encoded cytochrome c oxidase subunit 2 (MT-CO2, COXII) increased significantly in SY-SH5Y cells stimulated by α-Syn for 24h. Furthermore, the decline in ATP levels, the decreased mitochondrial membrane potential, and the enhanced reactive oxygen species in cells treated by α-Syn was reversed by inhibiting MT-CO2 gene expression. Subsequently, we observed that upregulation of MT-CO2 contributed to the release of cytochrome c and altered the levels of certain mitochondria-localized proteins, such as BCL2 family proteins. Therefore, we hypothesized that after being transferred into dopaminergic neurons, α-Syn injures mitochondria via activating MT-CO2. Our results suggested the initial step of the process by which α-Syn injures dopaminergic neurons and provides new therapeutic targets for α-Syn associated neurodegenerative disorders.
    Keywords:  SY-SH5Y cells; cytochrome c oxidase subunit 2; mitochondrial dysfunction; α-Synuclein
    DOI:  https://doi.org/10.1016/j.yexcr.2019.02.006
  7. Nat Commun. 2019 Feb 19. 10(1): 845
    Guo L, Cui C, Zhang K, Wang J, Wang Y, Lu Y, Chen K, Yuan J, Xiao G, Tang B, Sun Y, Wu C.
      Cell metabolism is strongly influenced by mechano-environment. We show here that a fraction of kindlin-2 localizes to mitochondria and interacts with pyrroline-5-carboxylate reductase 1 (PYCR1), a key enzyme for proline synthesis. Extracellular matrix (ECM) stiffening promotes kindlin-2 translocation into mitochondria and its interaction with PYCR1, resulting in elevation of PYCR1 level and consequent increase of proline synthesis and cell proliferation. Depletion of kindlin-2 reduces PYCR1 level, increases reactive oxygen species (ROS) production and apoptosis, and abolishes ECM stiffening-induced increase of proline synthesis and cell proliferation. In vivo, both kindlin-2 and PYCR1 levels are markedly increased in lung adenocarcinoma. Ablation of kindlin-2 in lung adenocarcinoma substantially reduces PYCR1 and proline levels, and diminishes fibrosis in vivo, resulting in marked inhibition of tumor growth and reduction of mortality rate. Our findings reveal a mechanoresponsive kindlin-2-PYCR1 complex that links mechano-environment to proline metabolism and signaling, and suggest a strategy to inhibit tumor growth.
    DOI:  https://doi.org/10.1038/s41467-019-08772-3
  8. Nat Cell Biol. 2019 Feb 18.
    Lystad AH, Carlsson SR, de la Ballina LR, Kauffman KJ, Nag S, Yoshimori T, Melia TJ, Simonsen A.
      Covalent modification of LC3 and GABARAP proteins to phosphatidylethanolamine in the double-membrane phagophore is a key event in the early phase of macroautophagy, but can also occur on single-membrane structures. In both cases this involves transfer of LC3/GABARAP from ATG3 to phosphatidylethanolamine at the target membrane. Here we have purified the full-length human ATG12-5-ATG16L1 complex and show its essential role in LC3B/GABARAP lipidation in vitro. We have identified two functionally distinct membrane-binding regions in ATG16L1. An N-terminal membrane-binding amphipathic helix is required for LC3B lipidation under all conditions tested. By contrast, the C-terminal membrane-binding region is dispensable for canonical autophagy but essential for VPS34-independent LC3B lipidation at perturbed endosomes. We further show that the ATG16L1 C-terminus can compensate for WIPI2 depletion to sustain lipidation during starvation. This C-terminal membrane-binding region is present only in the β-isoform of ATG16L1, showing that ATG16L1 isoforms mechanistically distinguish between different LC3B lipidation mechanisms under different cellular conditions.
    DOI:  https://doi.org/10.1038/s41556-019-0274-9
  9. Autophagy. 2019 Feb 17.
    Morita K, Hama Y, Mizushima N.
      Macroautophagy/autophagy requires many autophagy-related (ATG) proteins. Most of the ATG genes were identified by genetic screening using simple model organisms. Recently, we performed a forward genetic screen in mammalian cells using the CRISPR-Cas9 system and our autophagic flux reporter GFP-LC3-RFP. One of the identified proteins was TMEM41B, an ER-localized multi-spanning membrane protein. TMEM41B has a characteristic transmembrane domain (the VTT domain), which is also found in VMP1, another protein involved in autophagy. Our results show that TMEM41B and VMP1 are physically and functionally associated.
    Keywords:  CRISPR; DedA family; GFP-LC3-RFP reporter; VMP1; VTT domain; autophagosome formation; lipid droplet
    DOI:  https://doi.org/10.1080/15548627.2019.1582952
  10. J Gerontol A Biol Sci Med Sci. 2019 Feb 22. pii: glz056. [Epub ahead of print]
    Dumas SN, Lamming DW.
      Inhibition of mTORC1 (mechanistic Target Of Rapamycin Complex 1) with the pharmaceutical rapamycin prolongs the lifespan and healthspan of model organisms including rodents, with evidence now emerging that rapamycin and its analogs may also have rejuvenative effects in dogs and humans. However, the side effects associated with long-term rapamycin treatment, many of which are due to inhibition of a second mTOR complex, mTORC2, have seemed to preclude the routine use of rapamycin as a therapy for age-related diseases. Here, we discuss recent findings suggesting that strong, chronic inhibition of both mTOR complexes may not be necessary to realize the geroprotective effects of rapamycin. Instead, modestly but specifically inhibiting mTORC1 via a variety of emerging techniques, including intermittent or transient treatment with rapamycin derivatives, or specific dietary regimens, may be sufficient to promote health and longevity with reduced side effects. We will also discuss prospects for the development of new molecules that, by harnessing the detailed molecular understanding of mTORC1 signaling developed over the last decade, will provide new routes to the selective inhibition of mTORC1. We conclude that therapies based on the selective inhibition of mTORC1 may soon permit the safer treatment of diseases of aging.
    Keywords:  mTORC1; mTORC2; rapalog; rapamycin
    DOI:  https://doi.org/10.1093/gerona/glz056
  11. Cells. 2019 Feb 20. pii: E183. [Epub ahead of print]8(2):
    Lee DE, Bareja A, Bartlett DB, White JP.
      Skeletal muscle has remarkable regenerative capacity, relying on precise coordination between resident muscle stem cells (satellite cells) and the immune system. The age-related decline in skeletal muscle regenerative capacity contributes to the onset of sarcopenia, prolonged hospitalization, and loss of autonomy. Although several age-sensitive pathways have been identified, further investigation is needed to define targets of cellular dysfunction. Autophagy, a process of cellular catabolism, is emerging as a key regulator of muscle regeneration affecting stem cell, immune cell, and myofiber function. Muscle stem cell senescence is associated with a suppression of autophagy during key phases of the regenerative program. Macrophages, a key immune cell involved in muscle repair, also rely on autophagy to aid in tissue repair. This review will focus on the role of autophagy in various aspects of the regenerative program, including adult skeletal muscle stem cells, monocytes/macrophages, and corresponding age-associated dysfunction. Furthermore, we will highlight rejuvenation strategies that alter autophagy to improve muscle regenerative function.
    Keywords:  aging; caloric restriction; exercise; immune; macrophage; muscle regeneration; senescence; stem cell
    DOI:  https://doi.org/10.3390/cells8020183
  12. Bioorg Med Chem. 2019 Feb 16. pii: S0968-0896(19)30139-7. [Epub ahead of print]
    Kaiser N, Corkery D, Wu Y, Laraia L, Waldmann H.
      Autophagy ensures cellular homeostasis by the degradation of long-lived proteins, damaged organelles and pathogens. This catabolic process provides essential cellular building blocks upon nutrient deprivation. Cellular metabolism, especially mitochondrial respiration, has a significant influence on autophagic flux, and complex I function is required for maximal autophagy. In Parkinson's disease mitochondrial function is frequently impaired and autophagic flux is altered. Thus, dysfunctional organelles and protein aggregates accumulate and cause cellular damage. In order to investigate the interdependency between mitochondrial function and autophagy, novel tool compounds are required. Herein, we report the discovery of a structurally novel autophagy inhibitor (Authipyrin) using a high content screening approach. Target identification and validation led to the discovery that Authipyrin targets mitochondrial complex I directly, leading to the potent inhibition of mitochondrial respiration as well as autophagy.
    Keywords:  Autophagy; Complex I; Inhibitor; Mitochondrial respiration; Thienopyrimidines
    DOI:  https://doi.org/10.1016/j.bmc.2019.02.028
  13. J Cell Biol. 2019 Feb 20. pii: jcb.201809032. [Epub ahead of print]
    Shima T, Kirisako H, Nakatogawa H.
      A hallmark of autophagy is the de novo formation of double-membrane vesicles called autophagosomes, which sequester various cellular constituents for degradation in lysosomes or vacuoles. The membrane dynamics underlying the biogenesis of autophagosomes, including the origin of the autophagosomal membrane, are still elusive. Although previous studies suggested that COPII vesicles are closely associated with autophagosome biogenesis, it remains unclear whether these vesicles serve as a source of the autophagosomal membrane. Using a recently developed COPII vesicle-labeling system in fluorescence and immunoelectron microscopy in the budding yeast Saccharomyces cerevisiae, we show that the transmembrane cargo Axl2 is loaded into COPII vesicles in the ER. Axl2 is then transferred to autophagosome intermediates, ultimately becoming part of autophagosomal membranes. This study provides a definitive answer to a long-standing, fundamental question regarding the mechanisms of autophagosome formation by implicating COPII vesicles as a membrane source for autophagosomes.
    DOI:  https://doi.org/10.1083/jcb.201809032
  14. Cell Rep. 2019 Feb 19. pii: S2211-1247(19)30091-9. [Epub ahead of print]26(8): 2150-2165.e5
    Losier TT, Akuma M, McKee-Muir OC, LeBlond ND, Suk Y, Alsaadi RM, Guo Z, Reshke R, Sad S, Campbell-Valois FX, Gibbings DJ, Fullerton MD, Russell RC.
      The autophagy pathway is an essential facet of the innate immune response, capable of rapidly targeting intracellular bacteria. However, the initial signaling regulating autophagy induction in response to pathogens remains largely unclear. Here, we report that AMPK, an upstream activator of the autophagy pathway, is stimulated upon detection of pathogenic bacteria, before bacterial invasion. Bacterial recognition occurs through the detection of outer membrane vesicles. We found that AMPK signaling relieves mTORC1-mediated repression of the autophagy pathway in response to infection, positioning the cell for a rapid induction of autophagy. Moreover, activation of AMPK and inhibition of mTORC1 in response to bacteria is not accompanied by an induction of bulk autophagy. However, AMPK signaling is required for the selective targeting of bacteria-containing vesicles by the autophagy pathway through the activation of pro-autophagic kinase complexes. These results demonstrate a key role for AMPK signaling in coordinating the rapid autophagic response to bacteria.
    Keywords:  AMPK; OMV; Salmonella; ULK1; VPS34; autophagy; mTOR; outer membrane vesicles; xenophagy
    DOI:  https://doi.org/10.1016/j.celrep.2019.01.062
  15. J Cell Sci. 2019 Feb 20. pii: jcs222984. [Epub ahead of print]132(5):
    Heckmann BL, Green DR.
      Classically, canonical autophagy has been considered a survival mechanism initiated in response to nutrient insufficiency. We now understand that autophagy functions in multiple scenarios where it is necessary to maintain homeostasis. Recent evidence has established that a variety of non-canonical functions for autophagy proteins are mechanistically and functionally distinct from autophagy. LC3-associated phagocytosis (LAP) is one such novel function for autophagy proteins and is a contributor to immune regulation and inflammatory responses across various cell and tissue types. Characterized by the conjugation of LC3 family proteins to phagosome membranes, LAP uses a portion of the canonical autophagy machinery, following ligation of surface receptors that recognize a variety of cargos including pathogens, dying cells, soluble ligands and protein aggregates. However, instead of affecting canonical autophagy, manipulation of the LAP pathway in vivo alters immune activation and inflammatory responses. In this Cell Science at a Glance article and the accompanying poster, we detail the divergence of this distinctive mechanism from that of canonical autophagy by comparing and contrasting shared and unique components of each pathway.
    Keywords:  Autophagosome; Autophagy; LAPosome; LC3-associated phagocytosis; Phagocytosis
    DOI:  https://doi.org/10.1242/jcs.222984
  16. Nat Cell Biol. 2019 Feb 18.
    Nacarelli T, Lau L, Fukumoto T, Zundell J, Fatkhutdinov N, Wu S, Aird KM, Iwasaki O, Kossenkov AV, Schultz D, Noma KI, Baur JA, Schug Z, Tang HY, Speicher DW, David G, Zhang R.
      Cellular senescence is a stable growth arrest that is implicated in tissue ageing and cancer. Senescent cells are characterized by an upregulation of proinflammatory cytokines, which is termed the senescence-associated secretory phenotype (SASP). NAD+ metabolism influences both tissue ageing and cancer. However, the role of NAD+ metabolism in regulating the SASP is poorly understood. Here, we show that nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD+ salvage pathway, governs the proinflammatory SASP independent of senescence-associated growth arrest. NAMPT expression is regulated by high mobility group A (HMGA) proteins during senescence. The HMGA-NAMPT-NAD+ signalling axis promotes the proinflammatory SASP by enhancing glycolysis and mitochondrial respiration. HMGA proteins and NAMPT promote the proinflammatory SASP through NAD+-mediated suppression of AMPK kinase, which suppresses the p53-mediated inhibition of p38 MAPK to enhance NF-κB activity. We conclude that NAD+ metabolism governs the proinflammatory SASP. Given the tumour-promoting effects of the proinflammatory SASP, our results suggest that anti-ageing dietary NAD+ augmentation should be administered with precision.
    DOI:  https://doi.org/10.1038/s41556-019-0287-4
  17. Int J Mol Sci. 2019 Feb 19. pii: E901. [Epub ahead of print]20(4):
    Thellung S, Corsaro A, Nizzari M, Barbieri F, Florio T.
      The aim of this review is to critically analyze promises and limitations of pharmacological inducers of autophagy against protein misfolding-associated neurodegeneration. Effective therapies against neurodegenerative disorders can be developed by regulating the "self-defense" equipment of neurons, such as autophagy. Through the degradation and recycling of the intracellular content, autophagy promotes neuron survival in conditions of trophic factor deprivation, oxidative stress, mitochondrial and lysosomal damage, or accumulation of misfolded proteins. Autophagy involves the activation of self-digestive pathways, which is different for dynamics (macro, micro and chaperone-mediated autophagy), or degraded material (mitophagy, lysophagy, aggrephagy). All neurodegenerative disorders share common pathogenic mechanisms, including the impairment of autophagic flux, which causes the inability to remove the neurotoxic oligomers of misfolded proteins. Pharmacological activation of autophagy is typically achieved by blocking the kinase activity of mammalian target of rapamycin (mTOR) enzymatic complex 1 (mTORC1), removing its autophagy suppressor activity observed under physiological conditions; acting in this way, rapamycin provided the first proof of principle that pharmacological autophagy enhancement can induce neuroprotection through the facilitation of oligomers' clearance. The demand for effective disease-modifying strategies against neurodegenerative disorders is currently stimulating the development of a wide number of novel molecules, as well as the re-evaluation of old drugs for their pro-autophagic potential.
    Keywords:  autophagy; mTOR; neurodegenerative diseases; protein misfolding; rapamycin
    DOI:  https://doi.org/10.3390/ijms20040901