Article

Autophagy in Human Health and Disease

Department of Medicine, Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
New England Journal of Medicine (Impact Factor: 55.87). 02/2013; 368(7):651-62. DOI: 10.1056/NEJMra1205406
Source: PubMed
Download full-text

Full-text

Available from: Stefan W Ryter, Feb 01, 2015
  • Source
    • "Whether this conclusion would hold for all ALS-linked SOD1 mutants is unknown , but in our view it is more likely that they all cause the disease by the same basic mechanism rather than through several individual ones. Beclin 1 exerts its role in autophagy induction by being a membrane-bound scaffold which enables the recruitment of other autophagy proteins involved in nucleation and maturation of the autophagosome[12]. By binding to various specific proteins, Beclin can also localize to and regulate other vesicle trafficking pathways[37]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The motor system is selectively vulnerable to mutations in the ubiquitously expressed aggregation-prone enzyme superoxide dismutase-1 (SOD1). Autophagy clears aggregates, and factors involved in the process were analyzed in multiple areas of the CNS from human control subjects (n = 10) and amyotrophic lateral sclerosis (ALS) patients (n = 18) with or without SOD1 mutations. In control subjects, the key regulatory protein Beclin 1 and downstream factors were remarkably scarce in spinal motor areas. In ALS patients, there was evidence of moderate autophagy activation and also dysregulation. These changes were largest in SOD1 mutation carriers. To explore consequences of low autophagy capacity, effects of a heterozygous deletion of Beclin 1 were examined in ALS mouse models expressing mutant SOD1s. This caused earlier SOD1 aggregation, onset of symptoms, motor neuron loss, and a markedly shortened survival. In contrast, the levels of soluble misfolded SOD1 species were reduced. The findings suggest that an inherent low autophagy capacity might cause the vulnerability of the motor system, and that SOD1 aggregation plays a crucial role in the pathogenesis.
    Full-text · Article · Dec 2016
  • Source
    • "In autophagy, portions of membranes are sequestered at the cytosol and form a double membrane structure denominated autophagosomes (Kumar et al. 2013). The MAP-LC3 system acts as regulatory machinery in which the microtubule-associated protein 1 light chain 3B (LC3B) is a useful marker for identifying autophagosomes because it is located in their membranes (Choi et al. 2013; Tanida 2011). Autophagy plays an important role in the pathogenicity of many bacteria, and its study is increasing in order to understand whether the process acts against the pathogen, as a protective role in the host cell, or whether the pathogen takes advantage of it (Deretic and Levine 2009; Herr and Finley 2013; Liu and Klionsky 2015). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The MAP-LC3 system regulates the intracellular formation of autophagy-associated vacuoles. These vacuoles contain the LC3 protein; thus it has been utilized as a marker to identify autophagosomes. The aim of our study was to investigate whether Haemophilus influenzae strains and their supernatants could activate autophagy in human larynx carcinoma cell line (HEp-2). We demonstrate that higher expression of the LC3B-II protein was induced, particularly by nontypeable Haemophilus influenzae (NTHi) 49766 and by supernatants, containing <50 kDa proteins, of both strains. Ultrastructural studies demonstrate vacuoles with a double membrane and/or membrane material inside, showing similar features to those of autophagic vacuoles. Together, our findings demonstrate that H. influenzae strains and their supernatants trigger an autophagic process.
    Full-text · Article · Nov 2015 · Archives of Microbiology
  • Source
    • "However, the role of autophagy in cancer remains incompletely clear. In established tumours, some reports support that autophagy may offer a survival advantage on tumour cells, but contrasting findings also suggest that autophagy may also promote tumour cell death in apoptosis-resistant tumour cells (Choi et al., 2013). Thus, it is important to clarify the role of autophagy in different types of tumours. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Xanthohumol is the major prenylated flavonoid in the hop plant (Humulus lupulus L.). The aim of our study was to determine the effects of xanthohumol on the U87 glioma cell line. In the present study, the U87 glioma cell line was treated with xanthohumol. Our results showed that xanthohumol reduced cell viability and induced apoptosis detected by the MTT assay and PI-Annexin V doubling staining, respectively, in glioma cells. In the acridine orange staining experiments, we also found that xanthohumol induced autophagy, as detected by flow cytometry and confocal microscopy. Western blot also showed that xanthohumol inhibited the Akt/mTOR/S6K pathway and promoted LC3-II formation and p62 degradation. Moreover, we found that the Erk inhibitor or JNK inhibitor could partially reversed the xanthohumol-induced LC3-II formation and cell death. Otherwise, autophagy inhibition by bafilomycin A1, Atg5 shRNA, or Atg7 shRNA partially protected xanthohumol-induced cell death. These findings indicated that xanthohumol may induce glioma cell death through induction of autophagy. In addition, we also demonstrated that xanthohumol inhibited tumour growth in a mouse xenograft model. In conclusion, xanthohumol may induce autophagy in glioma cells through both Akt/mTOR/S6K pathway and MAPK cascade and inhibit tumour growth in vivo. Our findings also support that autophagy induction may provide benefits to increasing therapeutic efficacy of anti-cancer drugs for the treatment of glioblastoma multiforme.
    Full-text · Article · Oct 2015
Show more