Autophagy and apoptosis dysfunction in neurodegenerative disorders

Ghavami, Saeid; Shojaei, Shahla; Yeganeh, Behzad; Ande, Sudharsana Rao; Jangamreddy, Jaganmohan Reddy; Mehrpour, Maryam; Christoffersson, Jonas; Chaabane, Wiem; Moghadam, Adel Rezaei; Kashani, Hessam H; Hashemi, Mohammad; Owji, Ali Akbar; Łos, Marek

doi:10.1016/j.pneurobio.2013.10.004

Cited by 885 publications

(646 citation statements)

References 367 publications

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“…Many lines of evidence indicate that abnormal protein accumulation causes neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Under these pathological situations, several factors can disrupt lysosomal membrane integrity directly and induce rapid lysosomedependent cell death (26,27). In addition to lysosomal rupture, these pathologies may induce yet unknown damage to other organelles, and it is possible that FBXO27 migrates to the damaged organelles and causes the subsequent ubiquitination of glycoproteins.…”

Section: Discussionmentioning

confidence: 99%

Ubiquitination of exposed glycoproteins by SCF ^FBXO27 directs damaged lysosomes for autophagy

Yoshida

Yasuda

Fujita

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

103

120

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Ubiquitination functions as a signal to recruit autophagic machinery to damaged organelles and induce their clearance. Here, we report the characterization of FBXO27, a glycoprotein-specific F-box protein that is part of the SCF (SKP1/CUL1/F-box protein) ubiquitin ligase complex, and demonstrate that SCFFBXO27 ubiquitinates glycoproteins in damaged lysosomes to regulate autophagic machinery recruitment. Unlike F-box proteins in other SCF complexes, FBXO27 is subject to N-myristoylation, which localizes it to membranes, allowing it to accumulate rapidly around damaged lysosomes. We also screened for proteins that are ubiquitinated upon lysosomal damage, and identified two SNARE proteins, VAMP3 and VAMP7, and five lysosomal proteins, LAMP1, LAMP2, GNS, PSAP, and TMEM192. Ubiquitination of all glycoproteins identified in this screen increased upon FBXO27 overexpression. We found that the lysosomal protein LAMP2, which is ubiquitinated preferentially on lysosomal damage, enhances autophagic machinery recruitment to damaged lysosomes. Thus, we propose that SCFFBXO27 ubiquitinates glycoproteins exposed upon lysosomal damage to induce lysophagy.

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Section: Discussionmentioning

confidence: 99%

Ubiquitination of exposed glycoproteins by SCF ^FBXO27 directs damaged lysosomes for autophagy

Yoshida

Yasuda

Fujita

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

103

120

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“…42,43 The mTOR pathway can form 2 multiprotein complexes with distinct functionalities: mTORC1 (leads to Akt inhibition) and mTORC2 (leads to Akt activation). Phoshorylated Akt induces mTORC1 activation through intermediate molecules and Akt itself is phoshorylated by the mTORC2 complex.…”

Section: Discussionmentioning

confidence: 99%

Nuclear localized Akt enhances breast cancer stem-like cells through counter-regulation of p21^Waf1/Cip1and p27^kip1

et al. 2015

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Cancer stem-like cells (CSCs) are a rare subpopulation of cancer cells capable of propagating the disease and causing cancer recurrence. In this study, we found that the cellular localization of PKB/Akt kinase affects the maintenance of CSCs. When Akt tagged with nuclear localization signal (Akt-NLS) was overexpressed in SKBR3 and MDA-MB468 cells, these cells showed a 10-15% increase in the number of cells with CSCs enhanced ALDH activity and demonstrated a CD44 CHigh /CD24 ¡Low phenotype. This effect was completely reversed in the presence of Aktspecific inhibitor, triciribine. Furthermore, cells overexpressing Akt or Akt-NLS were less likely to be in G0/G1 phase of the cell cycle by inactivating p21 Waf1/Cip1 and exhibited increased clonogenicity and proliferation as assayed by colony-forming assay (mammosphere formation). Thus, our data emphasize the importance the intracellular localization of Akt has on stemness in human breast cancer cells. It also indicates a new robust way for improving the enrichment and culture of CSCs for experimental purposes. Hence, it allows for the development of simpler protocols to study stemness, clonogenic potency, and screening of new chemotherapeutic agents that preferentially target cancer stem cells. Summary: The presented data, (i) shows new, stemness-promoting role of nuclear Akt/PKB kinase, (ii) it underlines the effects of nuclear Akt on cell cycle regulation, and finally (iii) it suggests new ways to study cancer stem-like cells.

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“…Meanwhile, blockade of microglial autophagy in permanent middle cerebral artery occlusion by autophagy inhibitors reduces the severity of the disease [70] . Thus, autophagy in different diseases and cell types in the CNS seems to function differently.Autophagic cell death is still under debate and needs further investigation [71] . …”

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confidence: 99%

Role of autophagy in the pathogenesis of multiple sclerosis

Liang

2015

Neurosci. Bull.

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Autophagy plays an important role in maintaining the cellular homeostasis. One of its functions is to degrade unnecessary organelles and proteins for energy recycling or amino-acids for cell survival. Ablation of autophagy leads to neurodegeneration. Multiple sclerosis (MS), a permanent neurological impairment typical of chronic inflammatory demyelinating disorder, is an auto-immune disease of the central nervous system (CNS). Autophagy is tightly linked to the innate and adaptive immune systems during the autoimmune process, and several studies have shown that autophagy directly participates in the progress of MS or experimental autoimmune encephalomyelitis (EAE, a mouse model of MS). Dysfunction of mitochondria that intensively infl uences the autophagy pathway is one of the important factors in the pathogenesis of MS. Autophagy-related gene (ATG) 5 and immune-related GTPase M (IRGM) 1 are increased, while ATG16L2 is decreased, in T-cells in EAE and active relapsing-remitting MS brains. Administration of rapamycin, an inhibitor of mammalian target of rapamycin ( mTOR), ameliorates relapsing-remitting EAE. Infl ammation and oxidative stress are increased in MS lesions and EAE, but Lamp2 and the LC3-II/LC3-I ratio are decreased. Furthermore, autophagy in various glial cells plays important roles in regulating neuro-infl ammation in the CNS, implying potential roles in MS. In this review, we discuss the role of autophagy in the peripheral immune system and the CNS in neuroinfl ammation associated with the pathogenesis of MS. Keywords: autophagy; multiple sclerosis; neuro-infl ammation ·Review· IntroductionAutophagy, a lysosome-dependent degradation pathway, contributes to maintaining cellular homeostasis. Clearance of long-lived proteins, unnecessary organelles, and aggregate-prone proteins is mainly executed by autophagy for recycling cellular materials [1] . There are three subtypes of autophagy, macroautophagy, chaperone-mediated autophagy (CMA), and mitophagy. Macroautophagy is the major type for selective degradation of protein aggregates or misfolded proteins. The ubiquitin-labeled proteins are recognized by autophagy receptors, such as p62, neighbor of BRCA1 gene 1 (NBR1), and NIP3-like protein X (NIX), to form autophagosomes that then fuse with lysosomes for degradation. Many autophagy-related genes function during this process, such as Unc51-like kinase (ULK1) and autophagy-related gene (ATG) 5. Mammalian target of rapamycin (mTOR) represses autophagy by regulating ULK1 phosphorylation, while AMPK activates this process.CMA mediates the degradation of large molecular-weight proteins containing the KFERQ motif recognized by heat shock cognate protein of 70 kDa (HSC70). The substrate is then escorted to lysosome-associated membrane protein 2 (LAMP2A) for lysosomal degradation. Mitophagy is responsible for the degradation of damaged mitochondria.Parkin and PINK1 play critical roles in this process [2] . More Neurosci Bull August 1, 2015, 31(4): 435-444 436 attention has been paid to autophagy in the path...

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Autophagy and apoptosis dysfunction in neurodegenerative disorders

Cited by 885 publications

References 367 publications

Ubiquitination of exposed glycoproteins by SCF ^FBXO27 directs damaged lysosomes for autophagy

Ubiquitination of exposed glycoproteins by SCF ^FBXO27 directs damaged lysosomes for autophagy

Nuclear localized Akt enhances breast cancer stem-like cells through counter-regulation of p21^Waf1/Cip1and p27^kip1

Role of autophagy in the pathogenesis of multiple sclerosis

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Autophagy and apoptosis dysfunction in neurodegenerative disorders

Cited by 885 publications

References 367 publications

Ubiquitination of exposed glycoproteins by SCF FBXO27 directs damaged lysosomes for autophagy

Ubiquitination of exposed glycoproteins by SCF FBXO27 directs damaged lysosomes for autophagy

Nuclear localized Akt enhances breast cancer stem-like cells through counter-regulation of p21Waf1/Cip1and p27kip1

Role of autophagy in the pathogenesis of multiple sclerosis

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Ubiquitination of exposed glycoproteins by SCF ^FBXO27 directs damaged lysosomes for autophagy

Ubiquitination of exposed glycoproteins by SCF ^FBXO27 directs damaged lysosomes for autophagy

Nuclear localized Akt enhances breast cancer stem-like cells through counter-regulation of p21^Waf1/Cip1and p27^kip1