Impaired Degradation of Mutant α-Synuclein by Chaperone-Mediated Autophagy

Cuervo, Ana María; Stefanis, Leonidas; Fredenburg, Ross A.; Lansbury, Peter T.; Sulzer, David

doi:10.1126/science.1101738

Cited by 1,775 publications

(1,775 citation statements)

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“…Reduced tau‐P301L uptake is not caused by a problem in translocation across the lysosomal membrane, but rather by reduced targeting/binding to lysosomes, as we did not detect tau accumulation at the lysosomal membrane. This is in clear contrast to other pathogenic proteins such as mutant α‐synuclein or mutant LRRK2 that bind to lysosomes but fail to translocate through CMA (Cuervo et al ., 2004; Orenstein et al ., 2013). In the case of tau‐A152T, the dynamics of internalization/degradation through CMA were comparable to WT tau (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…6a–c). This finding rules out that diminished translocation could be due to oligomerization or aggregation of this mutant at the surface of lysosomes, which was previously described to be the case for pathogenic proteins such as α‐synuclein or LRRK2 (Cuervo et al ., 2004; Orenstein et al ., 2013). Although the tendency of hTau40 ΔK280 to aggregate could be the determinant of its poor clearance by CMA, we propose a direct effect of this mutation on tau's ability to undergo degradation through CMA, as inefficient CMA of hTau40 ΔK280 seems, in part, independent of aggregation.…”

Section: Resultsmentioning

confidence: 99%

“…We have selected N2a cells as experimental model to start understanding the complex interplay of tau proteins with autophagic pathways. Studies from our laboratories and others, with pathogenic proteins such as alpha‐synuclein, support that the mechanism of their toxic effect on autophagy is the same independent of the cell type (Cuervo et al ., 2004). However, future studies in transgenic mouse models expressing these tau variants are needed to confirm whether the toxic effect of P301L‐tau and A152T‐tau on autophagy that we describe here in N2a cells also occurs in these mouse neurons.…”

Section: Discussionmentioning

confidence: 99%

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Interplay of pathogenic forms of human tau with different autophagic pathways

et al. 2017

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SummaryLoss of neuronal proteostasis, a common feature of the aging brain, is accelerated in neurodegenerative disorders, including different types of tauopathies. Aberrant turnover of tau, a microtubule‐stabilizing protein, contributes to its accumulation and subsequent toxicity in tauopathy patients’ brains. A direct toxic effect of pathogenic forms of tau on the proteolytic systems that normally contribute to their turnover has been proposed. In this study, we analyzed the contribution of three different types of autophagy, macroautophagy, chaperone‐mediated autophagy, and endosomal microautophagy to the degradation of tau protein variants and tau mutations associated with this age‐related disease. We have found that the pathogenic P301L mutation inhibits degradation of tau by any of the three autophagic pathways, whereas the risk‐associated tau mutation A152T reroutes tau for degradation through a different autophagy pathway. We also found defective autophagic degradation of tau when using mutations that mimic common posttranslational modifications in tau or known to promote its aggregation. Interestingly, although most mutations markedly reduced degradation of tau through autophagy, the step of this process preferentially affected varies depending on the type of tau mutation. Overall, our studies unveil a complex interplay between the multiple modifications of tau and selective forms of autophagy that may determine its physiological degradation and its faulty clearance in the disease context.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Interplay of pathogenic forms of human tau with different autophagic pathways

et al. 2017

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“…This may include, for instance, alterations in the molecular crowding state due to cell shrinkage 2,19 or a breakdown of the α-Syn degradation mechanism. 20,21 Recent studies highlighted the enhanced aggregation propensity of α-Syn in the presence of interfaces such as lipid bilayers 22,23 or suggest a surface-assisted nucleation mechanism. 24 Indeed α-Syn oligomerization and aggregation in the presence of lipid vesicles or supported lipid bilayers (SLBs) has been described at significantly lower protein bulk concentrations, in the low micromolar range.…”

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confidence: 99%

On-Surface Aggregation of α-Synuclein at Nanomolar Concentrations Results in Two Distinct Growth Mechanisms

Rabe

Soragni

Reynolds

et al. 2013

ACS Chem. Neurosci.

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The aggregation of α-synuclein (α-Syn) is believed to be one of the key steps driving the pathology of Parkinson's disease and related neurodegenerative disorders. One of the present hypotheses is that the onset of such pathologies is related to the rise of α-Syn levels above a critical concentration at which toxic oligomers or mature fibrils are formed. In the present study, we find that α-Syn aggregation in vitro is a spontaneous process arising at bulk concentrations as low as 1 nM and below in the presence of both hydrophilic glass surfaces and cell membrane mimicking supported lipid bilayers (SLBs). Using three-dimensional supercritical angle fluorescence (3D-SAF) microscopy, we observed the process of α-Syn aggregation in situ. As soon as α-Syn monomers were exposed to the surface, they started to adsorb and aggregate along the surface plane without a prior lag phase. However, at a later stage of the aggregation process, a second type of aggregate was observed. In contrast to the first type, these aggregates showed an extended structure being tethered with one end to the surface and being mobile at the other end, which protruded into the solution. While both types of α-Syn aggregates were found to contain amyloid structures, their growing mechanisms turned out to be significantly different. Given the clear evidence that surface-induced α-Syn aggregation in vitro can be triggered at bulk concentrations far below physiological concentrations, the concept of a critical concentration initiating aggregation in vivo needs to be reconsidered.

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“…This brings up a second question: How would this aggregated a-syn be removed from the cell? Cuervo et al 6 have recently provided evidence that native wild-type a-syn is selectively translocated to lysosomes and normally degraded. It is not known whether the mature hyperphosphorylated inclusions are turning over in the affected cells, and to what extent they might be targeted to the lysosomal compartment for degradation.…”

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confidence: 99%