Abstract:
:The extensive autophagic-lysosomal pathology in Alzheimer disease (AD) brain has revealed a major defect: in the proteolytic clearance of autophagy substrates. Autophagy failure contributes on several levels to AD pathogenesis and has become an important therapeutic target for AD and other neurodegenerative diseases. We recently observed broad therapeutic effects of stimulating autophagic-lysosomal proteolysis in the TgCRND8 mouse model of AD that exhibits defective proteolytic clearance of autophagic substrates, robust intralysosomal amyloid-β peptide (Aβ) accumulation, extracellular β-amyloid deposition and cognitive deficits. By genetically deleting the lysosomal cysteine protease inhibitor, cystatin B (CstB), to selectively restore depressed cathepsin activities, we substantially cleared Aβ, ubiquitinated proteins and other autophagic substrates from autolysosomes/lysosomes and rescued autophagic-lysosomal pathology, as well as reduced total Aβ40/42 levels and extracellular amyloid deposition, highlighting the underappreciated importance of the lysosomal system for Aβ clearance. Most importantly, lysosomal remediation prevented the marked learning and memory deficits in TgCRND8 mice. Our findings underscore the pathogenic significance of autophagic-lysosomal dysfunction in AD and demonstrate the value of reversing this dysfunction as an innovative therapeautic strategy for AD.
journal_name
Autophagyjournal_title
Autophagyauthors
Yang DS,Stavrides P,Mohan PS,Kaushik S,Kumar A,Ohno M,Schmidt SD,Wesson DW,Bandyopadhyay U,Jiang Y,Pawlik M,Peterhoff CM,Yang AJ,Wilson DA,St George-Hyslop P,Westaway D,Mathews PM,Levy E,Cuervo AM,Nixon RAdoi
10.4161/auto.7.7.15596subject
Has Abstractpub_date
2011-07-01 00:00:00pages
788-9issue
7eissn
1554-8627issn
1554-8635pii
15596journal_volume
7pub_type
杂志文章相关文献
Autophagy文献大全abstract::Alzheimer disease (AD) is usually accompanied by two prominent pathological features, cerebral accumulation of amyloid-β (Aβ) plaques and presence of MAPT/tau neurofibrillary tangles. Dysregulated clearance of Aβ largely contributes to its accumulation and plaque formation in the brain. Macroautophagy/autophagy is a l...
journal_title:Autophagy
pub_type: 杂志文章
doi:10.1080/15548627.2021.1872187
更新日期:2021-01-19 00:00:00
abstract::The class III phosphatidylinositol (PtdIns)-3 kinase, PIK3C3/VPS34, forms multiple complexes and regulates a variety of cellular functions, especially in intracellular vesicle trafficking and autophagy. Even though PtdIns3P, the product of PIK3C3, is thought to be a critical membrane marker for the autophagosome, it i...
journal_title:Autophagy
pub_type: 杂志文章
doi:10.4161/auto.24877
更新日期:2013-07-01 00:00:00
abstract::Abnormal aggregation of SNCA/?-synuclein plays a crucial role in Parkinson disease (PD) pathogenesis. SNCA levels determine its toxicity, and its accumulation, even to a small extent, may be a risk factor for neurodegeneration. One of the main pathways for SNCA degradation is chaperone-mediated autophagy (CMA), a sele...
journal_title:Autophagy
pub_type: 杂志文章
doi:10.4161/auto.26451
更新日期:2013-12-01 00:00:00
abstract::Bulk degradation and nutrient recycling are events associated with autophagy. The core components of the autophagy machinery have been elucidated recently using molecular and genetic approaches. In particular, two ubiquitin-like proteins, ATG8 and ATG12, which conjugate with phosphatidylethanolamine (PE) and ATG5, res...
journal_title:Autophagy
pub_type: 杂志文章
doi:10.1105/tpc.110.075333
更新日期:2010-08-01 00:00:00
abstract::The critical role of the cellular autophagy pathway in viral infection and pathogenesis has become increasingly apparent. Mounting evidences suggest that viruses have developed different strategies to meticulously modulate intracellular autophagy for their own benefits, thereby either promoting efficient viral replica...
journal_title:Autophagy
pub_type: 杂志文章,评审
doi:10.4161/auto.5210
更新日期:2008-04-01 00:00:00
abstract::Regulated degradation of cellular components by lysosomes is essential to maintain biological homeostasis. In mammals, three forms of autophagy, macroautophagy, microautophagy and chaperone-mediated autophagy (CMA), have been identified. Here, we showed a novel type of autophagy, in which RNA is taken up directly into...
journal_title:Autophagy
pub_type: 杂志文章
doi:10.4161/auto.23002
更新日期:2013-03-01 00:00:00
abstract::ULK1 (unc-51 like autophagy activating kinase 1), the key mediator of MTORC1 signaling to autophagy, regulates early stages of autophagosome formation in response to starvation or MTORC1 inhibition. How ULK1 regulates the autophagy induction process remains elusive. Here, we identify that ATG13, a binding partner of U...
journal_title:Autophagy
pub_type: 杂志文章
doi:10.1080/15548627.2016.1140293
更新日期:2016-01-01 00:00:00
abstract::Macroautophagy is induced under various stresses to remove cytotoxic materials, including misfolded proteins and their aggregates. These protein cargoes are collected by specific autophagic receptors such as SQSTM1/p62 (sequestosome 1) and delivered to phagophores for lysosomal degradation. To date, little is known ab...
journal_title:Autophagy
pub_type: 杂志文章
doi:10.1080/15548627.2018.1491212
更新日期:2018-01-01 00:00:00
abstract::Based on my reading, and on my own experience, I have come to realize that people learn in different ways, and this can include the use of different media. This is one reason I have worked with various artists to portray the topic of autophagy through paintings, music and dance. Indeed, comments from members of the au...
journal_title:Autophagy
pub_type: 评论,社论
doi:10.1080/15548627.2019.1630225
更新日期:2019-09-01 00:00:00
abstract::Recent evidence suggests that autophagy may favor fibrosis through enhanced differentiation of fibroblasts in myofibroblasts. Here, we sought to characterize the mediators and signaling pathways implicated in autophagy-induced myofibroblast differentiation. Fibroblasts, serum starved for up to 4 d, showed increased LC...
journal_title:Autophagy
pub_type: 杂志文章
doi:10.4161/15548627.2014.981786
更新日期:2014-01-01 00:00:00
abstract:N:6-methyladenosine (m6A), the most abundant internal modification on mRNAs in eukaryotes, play roles in adipogenesis. However, the underlying mechanism remains largely unclear. Here, we show that m6A plays a critical role in regulating macroautophagy/autophagy and adipogenesis through targeting Atg5 and Atg7. Mechanis...
journal_title:Autophagy
pub_type: 杂志文章
doi:10.1080/15548627.2019.1659617
更新日期:2020-07-01 00:00:00
abstract::Coxsackievirus B3 (CVB3) has previously been shown to utilize autophagy in an advantageous manner during the course of infection of the host cell. However, few studies have determined whether stem cells induce autophagy in a similar fashion, and whether virus-induced autophagy occurs following infection of stem cells....
journal_title:Autophagy
pub_type: 杂志文章
doi:10.4161/auto.19781
更新日期:2012-06-01 00:00:00
abstract::Phagocytosis and macroautophagy/autophagy are 2 processes involved in lysosome-mediated clearance of extracellular and intracellular components, respectively. Recent studies have identified the recruitment of the autophagic protein LC3 during phagocytosis of apoptotic corpses in what is now called LC3-associated phago...
journal_title:Autophagy
pub_type: 杂志文章
doi:10.1080/15548627.2018.1512452
更新日期:2019-02-01 00:00:00
abstract::Flies expressing the most common Parkinson disease (PD)-related mutation, LRRK2-G2019S, in their dopaminergic neurons show loss of visual function and degeneration of the retina, including mitochondrial abnormalities, apoptosis and autophagy. Since the photoreceptors that degenerate are not dopaminergic, this demonstr...
journal_title:Autophagy
pub_type: 杂志文章
doi:10.4161/auto.24397
更新日期:2013-06-01 00:00:00
abstract::Degradation of intracellular components via macroautophagy is a complex multistep process that starts with the sequestration of cytosolic cargo in a de novo formed double-membrane vesicle or autophagosome. This compartment acquires the hydrolases required for cargo digestion by fusion with lysosomes. In contrast to th...
journal_title:Autophagy
pub_type: 杂志文章
doi:10.1096/fj.09-144519
更新日期:2010-08-01 00:00:00
abstract::Science informs art, and art informs science. Both processes involve creativity and imagination, and collaboration between scientists and artists often leads to new insights in both fields. We took advantage of the power of artistic imagery to demonstrate a dynamic cellular process, autophagy. In particular, we depict...
journal_title:Autophagy
pub_type: 杂志文章
doi:10.4161/auto.6.1.10812
更新日期:2010-01-01 00:00:00
abstract::Ultraviolet (UV)-induced DNA damage is a major risk factor for skin cancers including melanoma. UVRAG, originally identified to complement UV sensitivity in xeroderma pigmentosum (XP), has since been implicated in modulating macroautophagy/autophagy, in coordinating different intracellular trafficking pathways, and in...
journal_title:Autophagy
pub_type: 杂志文章
doi:10.1080/15548627.2016.1196319
更新日期:2016-09-01 00:00:00
abstract::Dysfunction of macroautophagy/autophagy has been postulated as a major cellular toxicological response to nanomaterials. It has been reported that excessive autophagy activation, induced by silica nanoparticles (SiNPs), contributes to autophagy dysfunction, whereas little is known how SiNPs trigger autophagy activatio...
journal_title:Autophagy
pub_type: 杂志文章
doi:10.1080/15548627.2020.1763019
更新日期:2020-05-23 00:00:00
abstract::We describe a protocol for rapid and efficient enrichment of autophagosomes from various tissues of the GFP-LC3 mouse. In order to increase the number of autophagosomes, we block autophagy flux in the GFP-LC3 mouse tissue with a single intraperitoneal injection of leupeptin 4-5 h before tissue harvesting. We homogeniz...
journal_title:Autophagy
pub_type: 杂志文章
doi:10.1080/15548627.2018.1539591
更新日期:2019-02-01 00:00:00
abstract::Although alterations of the macroautophagy/autophagy-lysosome pathway have been observed in cancer for many years, the mechanisms underlying these changes and the importance of autophagic and lysosomal reprogramming by cancer have yet to be well identified. Our recent study demonstrates that oncogenic BRAF signaling p...
journal_title:Autophagy
pub_type: 杂志文章
doi:10.1080/15548627.2019.1635386
更新日期:2019-10-01 00:00:00
abstract::As a selective degradation system, chaperone-mediated autophagy (CMA) is essential for maintaining cellular homeostasis and survival under stress conditions. Increasing evidence points to an important role for the dysfunction of CMA in the pathogenesis of Parkinson disease (PD). However, the mechanisms by which CMA re...
journal_title:Autophagy
pub_type: 杂志文章
doi:10.1080/15548627.2016.1179401
更新日期:2016-08-02 00:00:00
abstract::Some key questions being examined in the field of autophagy concern the origin of the membrane that forms the sequestering vesicle, the function of the related machinery, including the identification of new components and binding partners of previously identified autophagy-related proteins and the mechanism of autopha...
journal_title:Autophagy
pub_type:
doi:10.4161/auto.6.1.10819
更新日期:2010-01-01 00:00:00
abstract::Chronic drinking leads to myocardial contractile dysfunction where ethanol metabolism plays an essential role. Acetaldehyde, the main ethanol metabolite, mediates alcohol-induced cell injury although the underlying mechanism is still elusive. This study was designed to examine the mechanism involved in accelerated eth...
journal_title:Autophagy
pub_type: 杂志文章
doi:10.4161/auto.18997
更新日期:2012-04-01 00:00:00
abstract::The autophagy-lysosome system is essential for muscle cell homeostasis and its dysfunction has been linked to muscle disorders that are typically distinguished by massive autophagic buildup. Among them, glycogen storage disease type II (GSDII) is characterized by the presence of large glycogen-filled lysosomes in the ...
journal_title:Autophagy
pub_type: 杂志文章
doi:10.4161/auto.21691
更新日期:2012-11-01 00:00:00
abstract::Autophagy is involved with the turnover of intracellular components and the management of stress responses. Genetic studies in mice have shown that suppression of neuronal autophagy can lead to the accumulation of protein aggregates and neurodegeneration. However, no study has shown that increasing autophagic gene exp...
journal_title:Autophagy
pub_type: 杂志文章
doi:10.4161/auto.5269
更新日期:2008-02-01 00:00:00
abstract::Macroautophagy sequesters superflous cytosol and organelles into double-membraned autophagosomes. Over 30 autophagy-related (ATG) genes have been identified without elucidating the molecular details of autophagosome biogenesis. All proposed models for autophagosome formation require membrane fusion events (Fig. 1). Pr...
journal_title:Autophagy
pub_type: 杂志文章
doi:10.4161/auto.7.2.14383
更新日期:2011-02-01 00:00:00
abstract::The vascular system of plants consists of two conducting tissues, xylem and phloem, which differentiate from procambium cells. Xylem serves as a transporting system for water and signaling molecules and is formed by sequential developmental processes, including cell division/expansion, secondary cell wall deposition, ...
journal_title:Autophagy
pub_type: 杂志文章
doi:10.4161/auto.6.8.13429
更新日期:2010-11-01 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::Target of rapamycin complex 1 (TORC1) is an evolutionarily conserved protein kinase complex, whose activation in response to nutrients suppresses autophagy. In mammalian cells, amino-acid stimuli induce lysosomal translocation and activation of MTORC1 through the RRAG GTPase heterodimer, which is tethered to the surfa...
journal_title:Autophagy
pub_type: 评论,杂志文章
doi:10.1080/15548627.2018.1444313
更新日期:2018-01-01 00:00:00
abstract::Retinal ischemia is a major cause of vision loss and a common underlying mechanism associated with diseases, such as diabetic retinopathy and central retinal artery occlusion. We have previously demonstrated the robust neuroprotection in retina induced by post-conditioning (post-C), a brief period of ischemia, 24 h, f...
journal_title:Autophagy
pub_type: 杂志文章
doi:10.1080/15548627.2020.1767371
更新日期:2020-05-26 00:00:00