Autophagy-mediated clearance of aggresomes is not a universal phenomenon

Neurodegeneration Research Laboratory, National Neuroscience Institute, Singapore.
Human Molecular Genetics (Impact Factor: 6.39). 06/2008; 17(16):2570-82. DOI: 10.1093/hmg/ddn157
Source: PubMed


Aggresomes are juxtanuclear inclusion bodies that have been proposed to act as staging grounds for the disposal of protein aggregates via the autophagic route. To examine whether the composition of an aggresome influences its clearance by autophagy, we ectopically expressed a variety of aggregation-prone proteins in cultured cells to generate aggresomes that differ in their protein content. We found that whereas aggresomes generated in cells expressing mutant huntingtin or mutant tau, or co-expressing synphilin-1 and alpha-synuclein, are amenable to clearance by autophagy, those produced in AIMP2 (p38)- or mutant desmin-expressing cells are apparently resistant to autophagic clearance. Notably, AIMP2 (p38)- and desmin-positive inclusions fail to recruit key components of the autophagic/lysosomal system. However, by altering the composition of inclusions, 'autophagy-resistant' aggresomes could be rendered 'autophagy-susceptible'. Taken together, our results demonstrate that not all aggresomes are efficiently primed for autophagic clearance and highlight a certain degree of selectivity for the supposedly non-discriminative pathway.

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Article: Autophagy-mediated clearance of aggresomes is not a universal phenomenon

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    • "It is believed that aggresomes act as a cytoprotective method preventing the interaction of aberrant proteins with normal cellular molecules. Evidence also indicates that there is recruitment of UPS and lysosomes, suggesting that aggresomes can be digested by these two proteostasis mechanisms [108–110]. "
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    ABSTRACT: The misfolding, aggregation, and tissue accumulation of proteins are common events in diverse chronic diseases, known as protein misfolding disorders. Many of these diseases are associated with aging, but the mechanism for this connection is unknown. Recent evidence has shown that the formation and accumulation of protein aggregates may be a process frequently occurring during normal aging, but it is unknown whether protein misfolding is a cause or a consequence of aging. To combat the formation of these misfolded aggregates cells have developed complex and complementary pathways aiming to maintain protein homeostasis. These protective pathways include the unfolded protein response, the ubiquitin proteasome system, autophagy, and the encapsulation of damaged proteins in aggresomes. In this paper we review the current knowledge on the role of protein misfolding in disease and aging as well as the implication of deficiencies in the proteostasis cellular pathways in these processes. It is likely that further understanding of the mechanisms involved in protein misfolding and the natural defense pathways may lead to novel strategies for treatment of age-dependent protein misfolding disorders and perhaps aging itself.
    International Journal of Cell Biology 11/2013; 2013:638083. DOI:10.1155/2013/638083
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    • "This could obviously arise from gross autophagy system dysfunction, or alternately, from an inability of certain types of LB to recruit the autophagy apparatus efficiently, perhaps because (for some unknown reasons) they lacked the K63-linked ubiquitin tag, amongst other important autophagy recruitment components. Relevant to this, we have previously demonstrated that the composition of an aggresome influences its clearance by autophagy [45]. Notwithstanding the unresolved issues, our present study potentially offers a mechanistic explanation as to why parkin could afford considerable protection against proteasome dysfunction elicited by various endogenous or exogenous insults [29–31]. "
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    ABSTRACT: Disruption of the ubiquitin-proteasome system, which normally identifies and degrades unwanted intracellular proteins, is thought to underlie neurodegeneration. Supporting this, mutations of Parkin, a ubiquitin ligase, are associated with autosomal recessive parkinsonism. Remarkably, Parkin can protect neurons against a wide spectrum of stress, including those that promote proteasome dysfunction. Although the mechanism underlying the preservation of proteasome function by Parkin is hitherto unclear, we have previously proposed that Parkin-mediated K63-linked ubiquitination (which is usually uncoupled from the proteasome) may serve to mitigate proteasomal stress by diverting the substrate load away from the machinery. By means of linkage-specific antibodies, we demonstrated here that proteasome inhibition indeed promotes K63-linked ubiquitination of proteins especially in Parkin-expressing cells. Importantly, we further demonstrated that the recruitment of Ubc13 (an E2 that mediates K63-linked polyubiquitin chain formation exclusively) by Parkin is selectively enhanced under conditions of proteasomal stress, thus identifying a mechanism by which Parkin could promote K63-linked ubiquitin modification in cells undergoing proteolytic stress. This mode of ubiquitination appears to facilitate the subsequent clearance of Parkin substrates via autophagy. Consistent with the proposed protective role of K63-linked ubiquitination in times of proteolytic stress, we found that Ubc13-deficient cells are significantly more susceptible to cell death induced by proteasome inhibitors compared to their wild type counterparts. Taken together, our study suggests a role for Parkin-mediated K63 ubiquitination in maintaining cellular protein homeostasis, especially during periods when the proteasome is burdened or impaired.
    PLoS ONE 09/2013; 8(9):e73235. DOI:10.1371/journal.pone.0073235 · 3.23 Impact Factor
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    • "Thus, in the same experimental setting in which aggregates of a-synuclein, the main component of Lewy bodies in PD neurons, or of mutant huntingtin can be easily removed by macroautophagy, aggregates of proteins such as p38, which also accumulate in PD inclusions or desmin and are present in the aggregates of muscle dystrophies, remain undegraded even when macroautophagy is maximally activated. Failure to eliminate these aggregates by macroautophagy is not a result of poor degradation through this pathway; rather, these aggregates seem to completely escape the surveillance of the autophagic system as they cannot even be detected in autophagosomes (Wong et al. 2008). "

    Protein quality control in neurodegenerative diseases, 2013 edited by Morimoto RI, Christen Y, 12/2012: chapter Selective autophagy in cellular quality control: pages 63-75; Springer., ISBN: 978-3642279270
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