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Autophagy-mediated clearance of aggresomes is not a universal phenomenon

Neurodegeneration Research Laboratory, National Neuroscience Institute, Singapore.
Human Molecular Genetics (Impact Factor: 6.68). 06/2008; 17(16):2570-82. DOI: 10.1093/hmg/ddn157
Source: PubMed

ABSTRACT 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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    • "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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    • "Vimentin staining showed an altered structure of the intermediate filament network in cells with prominent perinuclear OPTN aggregation, another characteristic feature for aggresome formation (Fig. 1, lower panels). Therefore, similar to other aggregation-prone proteins associated with neurodegenerative diseases (Wong et al., 2008), OPTN can form aggresomes in mammalian cells when present at high concentrations. "
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    ABSTRACT: Many neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS) are linked to the accumulation of specific protein aggregates in affected regions of the nervous system. SOD1, TDP-43, FUS and optineurin (OPTN) proteins were identified to form intraneuronal inclusions in ALS patients. In addition, mutations in OPTN are associated with both ALS and glaucoma. Since the pathological role of OPTN in neuronal degeneration remains unresolved, we created a yeast model to study its potential for aggregation and toxicity. We observed that both wild type and disease-associated mutants of OPTN form toxic non-amyloid aggregates in yeast. Similar to reported cell culture and mouse models, the OPTN E50K mutant shows enhanced toxicity in yeast, implying a conserved gain-of-function mechanism. Furthermore, OPTN shows a unique aggregation pattern compared to other disease-related proteins in yeast. OPTN aggregates co-localize only partially with the Insoluble Protein Deposit site (IPOD) markers, but coincide perfectly with the prion seed-reducing protein Btn2 and several other aggregation-prone proteins, suggesting that protein aggregates are not limited to a single IPOD site. Importantly, changes in the Btn2p level modify OPTN toxicity and aggregation. This study generates a mechanistic framework for investigating how OPTN may trigger pathological changes in ALS and other OPTN-linked neurodegenerative disorders.
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    • "Alterations in the cellular systems responsible for quality control – chaperones and proteolytic systems – have been recently described to underlie the basis of different neurodegenerative disorders, or at least contribute to aggravate the course of the disease (Wong and Cuervo, 2010). Although macroautophagy can remove protein aggregates of mutant Htt (Iwata et al., 2005; Wong et al., 2008), primary defects in the autophagic machinery and its regulation in HD cells may limit the efficiency of this pathway as a cellular clearance mechanism (Martinez-Vicente et al., 2010). Cells often respond to compromise in one quality control pathway by upregulation of another (Massey et al., 2006; Kaushik et al., 2008; Kirkin et al., 2009; Korolchuk et al., 2009). "
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    ABSTRACT: Autophagy contributes to the removal of prone-to-aggregate proteins, but in several instances these pathogenic proteins have been shown to interfere with autophagic activity. In the case of Huntington's disease (HD), a congenital neurodegenerative disorder resulting from mutation in the huntingtin protein, we have previously described that the mutant protein interferes with the ability of autophagic vacuoles to recognize cytosolic cargo. Growing evidence supports the existence of cross talk among autophagic pathways, suggesting the possibility of functional compensation when one of them is compromised. In this study, we have identified a compensatory upregulation of chaperone-mediated autophagy (CMA) in different cellular and mouse models of HD. Components of CMA, namely the lysosome-associated membrane protein type 2A (LAMP-2A) and lysosomal-hsc70, are markedly increased in HD models. The increase in LAMP-2A is achieved through both an increase in the stability of this protein at the lysosomal membrane and transcriptional upregulation of this splice variant of the lamp-2 gene. We propose that CMA activity increases in response to macroautophagic dysfunction in the early stages of HD, but that the efficiency of this compensatory mechanism may decrease with age and so contribute to cellular failure and the onset of pathological manifestations.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 12/2011; 31(50):18492-505. DOI:10.1523/JNEUROSCI.3219-11.2011 · 6.75 Impact Factor
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