The chaperone-assisted selective autophagy complex dynamics and dysfunctions

Tedesco, B.; Vendredy, Leen; Timmerman, Vincent; Poletti, Angelo

doi:10.1080/15548627.2022.2160564

Cited by 39 publications

(26 citation statements)

References 267 publications

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“…Thus, our observation that HDAC6 pS22 is enriched within Lewy bodies is consistent with the constituent components of Lewy bodies having been trafficked there via the microtubule network. Previous observations of aggresomes indicate they are enriched for filamentous proteins that form a cage reminiscent of those previously described for Lewy bodies [22, 35]. Therefore, there are striking similarities between Lewy bodies and aggresomes, suggesting the formation of Lewy bodies is a deliberate response by neurons to a stressor.…”

Section: Discussionmentioning

confidence: 54%

“…As a previous study has reported mitochondria-enriched aggresomal structures in the context of mitophagy dysfunction, the present findings could be consistent with the accumulation of autophagic cargo due to α-synuclein aggregation causing autophagy dysfunction, from which the formation of a modified aggresome termed a Lewy body is a compensatory process to encapsulate autophagic cargo [37]. An alternative explanation is that α-synuclein aggregates are translocated to aggresomes, and that the presence of autophagic markers within Lewy bodies as presently reported is due to aggregates being trafficked within autophagosomes to the aggresome, as has been reported for other misfolded proteins [35]. Furthermore, the presence of autophagic mitochondria could be due to the presence of α-synuclein aggregates in damaged mitochondria, as has also been reported previously [38].…”

Section: Discussionmentioning

confidence: 94%

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Autophagic cargo in Lewy bodies: are Lewy bodies a compartment for spatial protein quality control?

Conod,

Charlesworth,

Palmowski

et al. 2023

Preprint

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Lewy bodies are neuropathologically associated with Lewy body dementia (LBD), but little is known about why they form or their role in the disease process. We previously reported Lewy bodies are a common feature of older individuals with primary mitochondrial diseases. However, as they are not an invariant finding, understanding differences between those with and without Lewy bodies may provide insights into factors that govern the formation of Lewy bodies in Lewy body disease (LBD). The present study sought to investigate whether deficient mitophagy in the context of mitochondrial dysfunction may underlie Lewy body formation. Post-mortem tissue was obtained from the cingulate gyrus and dorsal motor nucleus of the vagal nerve (DMV) of mitochondrial disease cases with Lewy bodies, primary mitochondrial disease cases without Lewy bodies, and control cases, in addition to LBD cases as comparison. An array of mitophagy and autophagy markers were quantified in 50 individual neurons per cingulate gyrus and all neurons per DMV using immunofluorescent analysis. No significant differences were found between groups, although there was a striking enrichment of markers of autophagic mitochondria and autophagic vesicles within Lewy bodies. Evaluation of diffuse α-synuclein aggregates, thought to precede Lewy body formation, suggested only autophagic mitochondria were present in early aggregates, perhaps suggesting sequestration of dysfunctional mitochondria is an early step in Lewy body formation. To characterise the composition of Lewy bodies, discovery proteomics was performed on isolated insoluble proteins from frozen cingulate gyrus, which identified up-regulation of markers of aggresomes, a regulated cellular response that occurs when protein degradative pathways become overwhelmed, a mechanism of spatial protein quality control (sPQC). Taken together, these findings are consistent with impairment of cellular waste handling pathways in Lewy body-bearing neurons, and that the formation of a Lewy body could be a deliberate cellular response to compartmentalise such waste.

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Section: Discussionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 94%

Autophagic cargo in Lewy bodies: are Lewy bodies a compartment for spatial protein quality control?

Conod,

Charlesworth,

Palmowski

et al. 2023

Preprint

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“…These Classes are “pre-initiation autophagy signaling”; “autophagophore initiation and elongation”; “autophagy substrate selection”; “autophagosome closure, maturation, and lysosome fusion”; “lysosomal catabolism”; and “autophagic lysosome reformation”. The remaining classes are “autophagy gene expression”, which comprises the transcription factors and transcriptional and translational regulators that control the expression of autophagy genes; “chaperone directed autophagy”, which includes components involved in chaperone-mediated autophagy 66 and chaperone assisted selective autophagy 67 ; and “specific function in autophagy unknown”, a small Class that contains components that clearly affect autophagy but through mechanisms that are not yet known. The Groups, Types, and Subtypes further specify a component’s function within the processes denoted by their Class.…”

Section: Resultsmentioning

confidence: 99%

A Comprehensive Enumeration of the Human Proteostasis Network. 2. Components of the Autophagy-Lysosome Pathway

Elsasser

Elia

Morimoto³

et al. 2023

Preprint

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The condition of having a healthy, functional proteome is known as protein homeostasis, or proteostasis. Establishing and maintaining proteostasis is the province of the proteostasis network, approximately 2,700 components that regulate protein synthesis, folding, localization, and degradation. The proteostasis network is a fundamental entity in biology that is essential for cellular health and has direct relevance to many diseases of protein conformation. However, it is not well defined or annotated, which hinders its functional characterization in health and disease. In this series of manuscripts, we aim to operationally define the human proteostasis network by providing a comprehensive, annotated list of its components. We provided in a previous manuscript a list of chaperones and folding enzymes as well as the components that make up the machineries for protein synthesis, protein trafficking into and out of organelles, and organelle-specific degradation pathways. Here, we provide a curated list of 838 unique high-confidence components of the autophagy-lysosome pathway, one of the two major protein degradation systems in human cells.

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“…Several proteins participate in selective autophagy, such as TAR DNA-binding protein 43 (TDP43), glucocerebrosidase (GBA), presenilin 1 (PSEN1), ATPase cation transporter 13A2 (ATP13A2), and superoxide dismutase-1 (SOD1) [ 29 ]. Selective autophagy processes contain proteins and specialized autophagic receptors which identify the cargo, generally mediated via cargo ubiquitination [ 30 ]. Through its interaction with a scaffold protein, the receptor either binds to cargoes or may be an integral component of these cargoes, connecting them to the autophagy machinery in the cell [ 31 ].…”

Section: Mechanism Of Autophagy Pathwaysmentioning

confidence: 99%

The Emerging Role of Autophagy as a Target of Environmental Pollutants: An Update on Mechanisms

Rahman

Parvez

et al. 2023

Toxics

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Autophagy is an evolutionarily conserved cellular system crucial for cellular homeostasis that protects cells from a broad range of internal and extracellular stresses. Autophagy decreases metabolic load and toxicity by removing damaged cellular components. Environmental contaminants, particularly industrial substances, can influence autophagic flux by enhancing it as a protective response, preventing it, or converting its protective function into a pro-cell death mechanism. Environmental toxic materials are also notorious for their tendency to bioaccumulate and induce pathophysiological vulnerability. Many environmental pollutants have been found to influence stress which increases autophagy. Increasing autophagy was recently shown to improve stress resistance and reduce genetic damage. Moreover, suppressing autophagy or depleting its resources either increases or decreases toxicity, depending on the circumstances. The essential process of selective autophagy is utilized by mammalian cells in order to eliminate particulate matter, nanoparticles, toxic metals, and smoke exposure without inflicting damage on cytosolic components. Moreover, cigarette smoke and aging are the chief causes of chronic obstructive pulmonary disease (COPD)-emphysema; however, the disease’s molecular mechanism is poorly known. Therefore, understanding the impacts of environmental exposure via autophagy offers new approaches for risk assessment, protection, and preventative actions which will counter the harmful effects of environmental contaminants on human and animal health.

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The chaperone-assisted selective autophagy complex dynamics and dysfunctions

Cited by 39 publications

References 267 publications

Autophagic cargo in Lewy bodies: are Lewy bodies a compartment for spatial protein quality control?

Autophagic cargo in Lewy bodies: are Lewy bodies a compartment for spatial protein quality control?

A Comprehensive Enumeration of the Human Proteostasis Network. 2. Components of the Autophagy-Lysosome Pathway

The Emerging Role of Autophagy as a Target of Environmental Pollutants: An Update on Mechanisms

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