Aggregate‐Prone Proteins Are Cleared from the Cytosol by Autophagy: Therapeutic Implications

Williams, Andrea; Jahreiss, Luca; Sarkar, Sovan; Saiki, Sachio; Menzies, Fiona M.; Ravikumar, Brinda; Rubinsztein, David C.

doi:10.1016/s0070-2153(06)76003-3

Cited by 276 publications

(211 citation statements)

References 40 publications

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“…Early reports have demonstrated and amyotrophic lateral sclerosis (ALS) [9,10] . Currently, many studies are dedicated to revealing the detailed mechanisms of the autophagic flux defects in those disorders to help identify possible therapeutic targets [8,11] .…”

Section: Autophagic Flux Defects In Neurodegenerative Diseasesmentioning

confidence: 99%

Why should autophagic flux be assessed?

et al. 2013

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As autophagy is involved in cell growth, survival, development and death, impaired autophagic flux has been linked to a variety of human pathophysiological processes, including neurodegeneration, cancer, myopathy, cardiovascular and immune-mediated disorders. There is a growing need to identify and quantify the status of autophagic flux in different pathological conditions. Given that autophagy is a highly dynamic and complex process that is regulated at multiple steps, it is often assessed accurately. This perspective review article will focus on the autophagic flux defects in different human disorders and update the current methods of monitoring autophagic flux. This knowledge is essential for developing autophagy-related therapeutics for treating the diseases.

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Section: Autophagic Flux Defects In Neurodegenerative Diseasesmentioning

confidence: 99%

Why should autophagic flux be assessed?

et al. 2013

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“…A considerable part of these diseases are associated with accumulation of proteins that are prone to aggregation due to mutation or misfolding. Protein aggregates can be sequestered and subsequently degraded by autophagosomes [196]. When their removal is perturbed, e.g., when autophagy is defective, they can be detrimental [197].…”

Section: Autophagy In Other Diseasesmentioning

confidence: 99%

“…Therefore, autophagy can prevent the emergence of neurodegenerative diseases. Indeed, autophagy protects against aggregation-prone mutant proteins in spinocerebellar ataxia, mutated forms of α-synuclein in Parkinson's disease, mutant Huntingtin in Huntington's disease, tau mutants that cause frontotemporal dementia, pathogenic intraneuronal amyloid beta in Alzheimer disease brain and polyglucosan inclusion bodies in Lafora disease [162,196,[198][199][200][201][202]. Interestingly, most of these neurodegenerative diseases are associated with decreased Beclin-1 levels, which might account for the impaired autophagic clearance.…”

Section: Autophagy In Other Diseasesmentioning

confidence: 99%

Autophagy: for better or for worse

et al. 2011

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Autophagy is a lysosomal degradation pathway that degrades damaged or superfluous cell components into basic biomolecules, which are then recycled back into the cytosol. In this respect, autophagy drives a flow of biomolecules in a continuous degradation-regeneration cycle. Autophagy is generally considered a pro-survival mechanism protecting cells under stress or poor nutrient conditions. Current research clearly shows that autophagy fulfills numerous functions in vital biological processes. It is implicated in development, differentiation, innate and adaptive immunity, ageing and cell death. In addition, accumulating evidence demonstrates interesting links between autophagy and several human diseases and tumor development. Therefore, autophagy seems to be an important player in the life and death of cells and organisms. Despite the mounting knowledge about autophagy, the mechanisms through which the autophagic machinery regulates these diverse processes are not entirely understood. In this review, we give a comprehensive overview of the autophagic signaling pathway, its role in general cellular processes and its connection to cell death. In addition, we present a brief overview of the possible contribution of defective autophagic signaling to disease.

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“…[19][20][21][22] Rapamycin was shown by Rubinsztein and colleagues in cell and animal models to stimulate the clearance of protein aggregates and to protect neurons against the cytotoxicity caused by such aggregation-prone proteins. 23 Beneficial effects of rapamycin have also been reported in animal models of a wide range of neurodegenerative diseases, including Parkinson, Alzheimer, and Huntington diseases, as well as amyotrophic lateral sclerosis. 24 In addition, rapamycin administration was reported to extend life span in lower organisms and even mice, 25 as was the genetic downregulation of MTOR, probably through decreasing MTORC1.…”

mentioning

confidence: 99%

Coordinate regulation of autophagy and the ubiquitin proteasome system by MTOR

Zhao

Goldberg

2016

Autophagy

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Proteins in eukaryotic cells are continually being degraded to amino acids either by the ubiquitin proteasome system (UPS) or by the autophagic-lysosomal pathway. The breakdown of proteins by these 2 degradative pathways involves totally different enzymes that function in distinct subcellular compartments. While most studies of the UPS have focused on the selective ubiquitination and breakdown of specific cell proteins, macroautophagy/autophagy is a more global nonselective process. Consequently, the UPS and autophagy were traditionally assumed to serve distinct physiological functions and to be regulated in quite different manners. However, recent findings indicate that protein breakdown by these 2 systems is coordinately regulated by important physiological stimuli. The activation of MTORC1 by nutrients and hormones rapidly suppresses proteolysis by both proteasomes and autophagy, which helps promote protein accumulation, whereas in nutrient-poor conditions, MTORC1 inactivation causes the simultaneous activation of these 2 degradative pathways to supply the deprived cells with a source of amino acids. Also this selective breakdown of key anabolic proteins by the UPS upon MTORC1 inhibition can help limit growth-related processes (e.g., cholesterol biosynthesis). Thus, the collaboration of these 2 degradative systems, together with the simultaneous control of protein translation by MTORC1, provide clear advantages to the organism in both growth and starvation conditions.

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Aggregate‐Prone Proteins Are Cleared from the Cytosol by Autophagy: Therapeutic Implications

Cited by 276 publications

References 40 publications

Why should autophagic flux be assessed?

Why should autophagic flux be assessed?

Autophagy: for better or for worse

Coordinate regulation of autophagy and the ubiquitin proteasome system by MTOR

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