Abstract:
:SNCA/α-synuclein aggregation plays a crucial role in synucleinopathies such as Parkinson disease and dementia with Lewy bodies. Aggregating and nonaggregating SNCA species are degraded by the autophagy-lysosomal pathway (ALP). Previously, we have shown that the ALP is not only responsible for SNCA degradation but is also involved in the intracellular aggregation process of SNCA. An additional role of extracellular SNCA in the pathology of synucleinopathies substantiating a prion-like propagation hypothesis has been suggested since released SNCA species and spreading of SNCA pathology throughout neural cells have been observed. However, the molecular interplay between intracellular pathways, SNCA aggregation, release, and response of the local microenvironment remains unknown. Here, we attributed SNCA-induced toxicity mainly to secreted species in a cell culture model of SNCA aggregation and in SNCA transgenic mice: We showed that ALP inhibition by bafilomycinA1 reduced intracellular SNCA aggregation but increased secretion of smaller oligomers that exacerbated microenvironmental response including uptake, inflammation, and cellular damage. Low-aggregated SNCA was predominantly released by exosomes and RAB11A-associated pathways whereas high-aggregated SNCA was secreted by membrane shedding. In summary, our study revealed a novel role of the ALP by linking protein degradation to nonclassical secretion for toxic SNCA species. Thus, impaired ALP in the diseased brain not only limits intracellular degradation of misfolded proteins, but also leads to a detrimental microenvironmental response due to enhanced SNCA secretion. These findings suggest that the major toxic role of SNCA is related to its extracellular species and further supports a protective role of intracellular SNCA aggregation.
journal_name
Autophagyjournal_title
Autophagyauthors
Poehler AM,Xiang W,Spitzer P,May VE,Meixner H,Rockenstein E,Chutna O,Outeiro TF,Winkler J,Masliah E,Klucken Jdoi
10.4161/auto.36436subject
Has Abstractpub_date
2014-01-01 00:00:00pages
2171-92issue
12eissn
1554-8627issn
1554-8635journal_volume
10pub_type
杂志文章相关文献
Autophagy文献大全abstract::Cargo-based assays have proven invaluable in the study of macroautophagy in yeast and mammalian cells. Proteomic analysis of autolysosomes identified the metabolic enzyme, betaine homocysteine methyltransferase (BHMT), as a potential cargo-based, end-point marker for mammalian macroautophagy. To test whether degradati...
journal_title:Autophagy
pub_type: 杂志文章
doi:10.4161/auto.5275
更新日期:2008-02-01 00:00:00
abstract::Nutrients not only act as building blocks but also as signaling molecules. Nutrient-availability promotes cell growth and proliferation and suppresses catabolic processes, such as macroautophagy/autophagy. These effects are mediated by checkpoint kinases such as MTOR (mechanistic target of rapamycin kinase), which is ...
journal_title:Autophagy
pub_type: 杂志文章
doi:10.1080/15548627.2020.1783119
更新日期:2020-07-05 00:00:00
abstract::Neuroepithelial cells undergoing differentiation efficiently remodel their cytoskeleton and shape in an energy-consuming process. The capacity of autophagy to recycle cellular components and provide energy could fulfill these requirements, thus supporting differentiation. However, little is known regarding the role of...
journal_title:Autophagy
pub_type: 杂志文章
doi:10.4161/auto.8.2.18535
更新日期:2012-02-01 00:00:00
abstract::The initiation of macroautophagy/autophagy is tightly regulated by the upstream ULK1 kinase complex, which affects many downstream factors including the PtdIns3K complex. The phosphorylation of the right position at the right time on downstream molecules is governed by proper complex formation. One component of the UL...
journal_title:Autophagy
pub_type: 杂志文章
doi:10.1080/15548627.2018.1504716
更新日期:2018-01-01 00:00:00
abstract::Phagocytosis plays a central role in immunity and tissue homeostasis. After internalization of cargo into single-membrane phagosomes, these compartments undergo a maturation sequences that terminates in lysosome fusion and cargo degradation. Components of the autophagy pathway have recently been linked to phagosome ma...
journal_title:Autophagy
pub_type: 杂志文章
doi:10.1080/15548627.2016.1191724
更新日期:2016-09-01 00:00:00
abstract::Mechanisms to protect against viral infections are crucial during pregnancy as maternal-fetal transmission can have serious pathological outcomes, including fetal infection and its sequelae, such as growth restriction, birth defects, and/or fetal death. The trophoblast forms the interface between the feto-placental un...
journal_title:Autophagy
pub_type: 杂志文章
doi:10.4161/auto.26558
更新日期:2013-12-01 00:00:00
abstract::The two structurally related, major lysosomal membrane proteins LAMP-1 and LAMP-2 were for a long time regarded as crucial for the protection of the lysosomal membrane from the hostile lumenal environment. However, recent studies on the effects of single and combined LAMP-deficiency in mice reveal alternative function...
journal_title:Autophagy
pub_type: 杂志文章
doi:10.4161/auto.5724
更新日期:2008-05-01 00:00:00
abstract::Cytotoxic necrotizing factor 1 is a bacterial protein toxin from Escherichia coli that is able to activate the Rho GTPases and to hinder apoptosis and mitotic catastrophe. Upon exposure to toxin, cells undergo a complex framework of changes, including cytoskeleton remodeling and multinucleation. These cells also show ...
journal_title:Autophagy
pub_type: 杂志文章
doi:10.4161/auto.2965
更新日期:2006-10-01 00:00:00
abstract::Heme is an essential molecule expressed in many tissues where it plays key roles as the prosthetic group of several proteins involved in vital physiological and metabolic processes such as gas and electron transport. Structurally, heme is a tetrapyrrole ring containing an atom of iron (Fe) in its center. When released...
journal_title:Autophagy
pub_type: 杂志文章
doi:10.1080/15548627.2016.1271515
更新日期:2017-03-04 00:00:00
abstract::Infection and inflammation are able to induce diet-independent Na+-accumulation without commensurate water retention in afflicted tissues, which favors the pro-inflammatory activation of mouse macrophages and augments their antibacterial and antiparasitic activity. While Na+-boosted host defense against the protozoan ...
journal_title:Autophagy
pub_type: 杂志文章
doi:10.1080/15548627.2019.1596483
更新日期:2019-11-01 00:00:00
abstract::Autophagy helps to maintain cellular homeostasis by removing misfolded proteins and damaged organelles, and generally acts as a cytoprotective mechanism for neuronal survival. Here we showed that mice deficient in the Vici syndrome gene Epg5, which is required for autophagosome maturation, show accumulation of ubiquit...
journal_title:Autophagy
pub_type: 杂志文章
doi:10.1080/15548627.2016.1238554
更新日期:2016-12-01 00:00:00
abstract::In a recent paper we addressed the mechanism by which defective autophagy contributes to TARDBP/TDP-43-mediated neurodegenerative disorders. We demonstrated that TARDBP regulates MTORC1-TFEB signaling by targeting RPTOR/raptor, a key component and an adaptor protein of MTORC1. Loss of TARDBP decreased the mRNA stabili...
journal_title:Autophagy
pub_type: 杂志文章
doi:10.1080/15548627.2016.1151596
更新日期:2016-01-01 00:00:00
abstract::(Macro)autophagy is a membrane-trafficking process that serves to sequester cellular constituents in organelles termed autophagosomes, which target their degradation in the lysosome. Autophagy operates at basal levels in all cells where it serves as a homeostatic mechanism to maintain cellular integrity. The levels an...
journal_title:Autophagy
pub_type: 杂志文章
doi:10.4161/auto.7.11.16646
更新日期:2011-11-01 00:00:00
abstract::We have reported in a variety of mammalian cells the reversible formation of a filamentous actin (F-actin)-enriched aggresome generated by the actin toxin jasplakinolide (Lázaro-Diéguez et al., J Cell Sci 2008; 121:1415-25). Notably, this F-actin aggresome (FAG) resembles in many aspects the pathological Hirano body, ...
journal_title:Autophagy
pub_type: 杂志文章
doi:10.4161/auto.6345
更新日期:2008-07-01 00:00:00
abstract::Autophagy genes were first identified in the yeast system and some of their mammalian orthologues have also been characterized. Increasing lines of evidence indicate that various intracellular proteins, including G proteins, mammalian target of rapamycin (mTor) and Pl3K/Akt/PKB, of transmembrane signaling pathways are...
journal_title:Autophagy
pub_type: 评论,杂志文章,评审
doi:10.4161/auto.3427
更新日期:2007-01-01 00:00:00
abstract::In yeast, Tom22, the central component of the TOMM (translocase of outer mitochondrial membrane) receptor complex, is responsible for the recognition and translocation of synthesized mitochondrial precursor proteins, and its protein kinase CK2-dependent phosphorylation is mandatory for TOMM complex biogenesis and prop...
journal_title:Autophagy
pub_type: 杂志文章
doi:10.1080/15548627.2017.1403716
更新日期:2018-01-01 00:00:00
abstract::Accumulating evidence has demonstrated that macroautophagy/autophagy plays an essential role in self-renewal and differentiation in embryonic hematopoiesis. Here, according to the RNA sequencing data sets of 5 population cells related to hematopoietic stem cell (HSC) formation during mouse embryogenesis (endothelial c...
journal_title:Autophagy
pub_type: 杂志文章
doi:10.1080/15548627.2016.1278093
更新日期:2017-04-03 00:00:00
abstract::The acetylase inhibitor, spermidine and the deacetylase activator, resveratrol, both induce autophagy and prolong life span of the model organism Caenorhabditis elegans in an autophagydependent fashion. Based on these premises, we investigated the differences and similarities in spermidine and resveratrol-induced auto...
journal_title:Autophagy
pub_type: 杂志文章
doi:10.4161/auto.7.6.15191
更新日期:2011-06-01 00:00:00
abstract::Autophagy acts as an intrinsic defense system against intracellular bacterial survival. Recently, multiple cellular pathways that target intracellular bacterial pathogens to autophagy have been described. These include the Atg5/LC3 pathway, which targets Shigella, the ubiquitin (Ub)-NDP52-LC3 pathway, which targets Gr...
journal_title:Autophagy
pub_type: 杂志文章,评审
doi:10.4161/auto.7.3.14581
更新日期:2011-03-01 00:00:00
abstract::Macroautophagy/autophagy involves the formation of an autophagosome, a double-membrane vesicle that delivers sequestered cytoplasmic cargo to lysosomes for degradation and recycling. Closely related, endocytosis mediates the sorting and transport of cargo throughout the cell, and both processes are important for cellu...
journal_title:Autophagy
pub_type: 杂志文章
doi:10.1080/15548627.2017.1356976
更新日期:2017-10-03 00:00:00
abstract::Autophagy is a highly conserved intracellular degradation system, and recently was shown to display circadian rhythms in mice. The mechanisms underlying circadian regulation of autophagy, however, are still unclear. Here, we observed that numbers of autophagosomes and autolysosomes exhibit daily rhythms in the zebrafi...
journal_title:Autophagy
pub_type: 杂志文章
doi:10.1080/15548627.2016.1183843
更新日期:2016-08-02 00:00:00
abstract::Silver nanoparticles (Ag NPs) are cytotoxic to cancer cells and possess excellent potential as an antitumor agent. A variety of nanoparticles have been shown to induce autophagy, a critical cellular degradation process, and the elevated autophagy in most of these situations promotes cell death. Whether Ag NPs can indu...
journal_title:Autophagy
pub_type: 杂志文章
doi:10.4161/auto.36293
更新日期:2014-01-01 00:00:00
abstract::Efavirenz (EFV) is the most widely used non-nucleoside reverse transcriptase inhibitor applied in highly active antiretroviral therapy (HAART), the combined pharmacological treatment of the human immunodeficiency virus infection. Its use has been associated with the development of several adverse events including hepa...
journal_title:Autophagy
pub_type: 杂志文章
doi:10.4161/auto.7.11.17653
更新日期:2011-11-01 00:00:00
abstract::Autophagy is a conserved homeostatic process in which cytoplasmic contents are degraded and recycled. Two ubiquitin-like conjugation pathways are required for the generation of autophagosomes, and ATG5 is necessary for both of these processes. Studies of mice deficient in ATG5 reveal a key role for autophagy in T lymp...
journal_title:Autophagy
pub_type: 杂志文章
doi:10.4161/auto.23484
更新日期:2013-04-01 00:00:00
abstract::Here, we present a summary of our recent findings on the (patho-)physiological relevance of PINK1-phosphorylated ubiquitin (p-S65-Ub). Using novel polyclonal antibodies, we find that p-S65-Ub specifically accumulates on damaged mitochondria. Phosphorylation of ubiquitin on serine 65 depends on the activity of PINK1 an...
journal_title:Autophagy
pub_type: 杂志文章
doi:10.1080/15548627.2015.1091912
更新日期:2015-11-02 00:00:00
abstract::Autophagy is one of the survival processes of cancer cells, especially in stressful conditions such as starvation, hypoxia and chemotherapeutic agents. However, its roles in tumor survival have not yet been fully elucidated. Here, we found for the first time that JAK2/STAT3 was activated in HeLa cells when they were s...
journal_title:Autophagy
pub_type: 杂志文章
doi:10.4161/auto.6.8.13547
更新日期:2010-11-01 00:00:00
abstract::To study mitochondrial protein age dynamics, we targeted a time-sensitive fluorescent protein, MitoTimer, to the mitochondrial matrix. Mitochondrial age was revealed by the integrated portions of young (green) and old (red) MitoTimer protein. Mitochondrial protein age was dependent on turnover rates as pulsed synthesi...
journal_title:Autophagy
pub_type: 杂志文章
doi:10.4161/auto.26503
更新日期:2013-11-01 00:00:00
abstract::Macroautophagy/autophagy dysfunction is associated with many neurodegenerative diseases. TFEB (transcription factor EB), an important molecule that regulates lysosomal and autophagy function, is regarded as a potential target for treating some neurodegenerative diseases. However, the relationship between autophagy dys...
journal_title:Autophagy
pub_type: 杂志文章
doi:10.1080/15548627.2019.1569926
更新日期:2019-06-01 00:00:00
abstract::Post-translational modifications of autophagy-related (ATG) genes are necessary to modulate their functions. However, ATG protein methylation and its physiological role have not yet been elucidated. The methylation of non-histone proteins by SETD7, a SET domain-containing lysine methyltransferase, is a novel regulator...
journal_title:Autophagy
pub_type: 杂志文章
doi:10.1080/15548627.2017.1389357
更新日期:2018-01-01 00:00:00
abstract::During (macro)autophagy, cells form transient organelles, termed autophagosomes, to target a broad spectrum of substrates for degradation critical to cellular and organismal health. Driven by rapid membrane assembly, an initially small vesicle (phagophore) elongates into a large cup-shaped structure to engulf substrat...
journal_title:Autophagy
pub_type: 杂志文章
doi:10.1080/15548627.2020.1725379
更新日期:2020-04-01 00:00:00