Interplay of LRRK2 with chaperone-mediated autophagy

Orenstein, Samantha J.; Kuo, Sheng‐Han; Tasset, Inmaculada; Arias, Esperanza; Koga, Hiroshi; Fernández-Carasa, Irene; Cortés, Etty; Honig, Lawrence S.; Dauer, William T.; Consiglio, Antonella; Raya, Ángel; Sulzer, David; Cuervo, Ana María

doi:10.1038/nn.3350

Cited by 510 publications

(497 citation statements)

References 55 publications

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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%

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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%

Interplay of pathogenic forms of human tau with different autophagic pathways

et al. 2017

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“…Such mishandling of aberrant proteins alters proteostasis and often leads to the precipitation of protein aggregates that contribute to neuronal demise [49]. The involvement of CMA in neurodegeneration is two-fold, as it contributes to the elimination of pathogenic proteins, but also often, becomes victim of the toxic effect of these aberrant proteins [50][51][52][53]. This dual role of CMA in neurodegenerative disorders makes it necessary to analyze the status of this autophagy pathway in disease in order to determine whether interventions aimed at enhancing CMA activity could be of potential value or not, depending on the degree of compromise of this pathway and the reversibility of the CMA blockage.…”

Section: Reduced Cma and Neurodegenerationmentioning

confidence: 99%

Chaperone-mediated autophagy: roles in disease and aging

2013

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This review focuses on chaperone-mediated autophagy (CMA), one of the proteolytic systems that contributes to degradation of intracellular proteins in lysosomes. CMA substrate proteins are selectively targeted to lysosomes and translocated into the lysosomal lumen through the coordinated action of chaperones located at both sides of the membrane and a dedicated protein translocation complex. The selectivity of CMA permits timed degradation of specific proteins with regulatory purposes supporting a modulatory role for CMA in enzymatic metabolic processes and subsets of the cellular transcriptional program. In addition, CMA contributes to cellular quality control through the removal of damaged or malfunctioning proteins. Here, we describe recent advances in the understanding of the molecular dynamics, regulation and physiology of CMA, and discuss the evidence in support of the contribution of CMA dysfunction to severe human disorders such as neurodegeneration and cancer.

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“…A recent investigation of leucine-rich repeat kinase 2 (LRRK2), mutation of which is linked to PD, showed that it is a CMA substrate [56] . LRRK2 G2019S, the most common mutant form, is poorly degraded by this pathway.…”

Section: Parkinson's Disease (Pd)mentioning

confidence: 99%

“…This decrease is in part due to the accelerated removal of oxidized MEF2D by CMA. Consistently, the levels of oxidized MEF2D are much higher in the postmortem PD brain than in controls, consistent with the notion that reduced CMA in PD leads to the accumulation of damaged MEF2D, disrupting its homeostasis and function.A recent investigation of leucine-rich repeat kinase 2 (LRRK2), mutation of which is linked to PD, showed that it is a CMA substrate [56] . LRRK2 G2019S, the most common mutant form, is poorly degraded by this pathway.…”

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confidence: 99%

Chaperone-mediated autophagy: roles in neuroprotection

et al. 2015

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Chaperone-mediated autophagy (CMA), one of the main pathways of lysosomal proteolysis, is characterized by the selective targeting and direct translocation into the lysosomal lumen of substrate proteins containing a targeting motif biochemically related to the pentapeptide KFERQ. Along with the other two lysosomal pathways, macro-and micro-autophagy, CMA is essential for maintaining cellular homeostasis and survival by selectively degrading misfolded, oxidized, or damaged cytosolic proteins. CMA plays an important role in pathologies such as cancer, kidney disorders, and neurodegenerative diseases. Neurons are post-mitotic and highly susceptible to dysfunction of cellular quality-control systems. Maintaining a balance between protein synthesis and degradation is critical for neuronal functions and homeostasis. Recent studies have revealed several new mechanisms by which CMA protects neurons through regulating factors critical for their viability and homeostasis. In the current review, we summarize recent advances in the understanding of the regulation and physiology of CMA with a specifi c focus on its possible roles in neuroprotection.Keywords: chaperone-mediated autophagy; cellular homeostasis; neuroprotection; neuronal death; neurodegenerative disease ·Review· IntroductionMaintaining the balance between protein synthesis and degradation contributes to cellular homeostasis [1][2][3] . The ubiquitin-proteasome system (UPS) and the autophagylysosome pathway (ALP) are major systems present in almost all cell types to mediate the degradation of intracellular proteins into their constitutive amino-acids [4,5] .The UPS is a multi-subunit protease complex that degrades proteins tagged with one or more covalently-bound ubiquitin molecules, and most proteasome substrates are proteins with a short half-life [6,7] .In contrast to the UPS, the ALP is mainly responsible for the degradation of long-lived proteins and organelles.On the basis of the mechanism used for delivery of intracellular cargoes to lysosomes, autophagy can be divided into three types: macroautophagy (MA), microautophagy, and chaperone-mediated autophagy (CMA) [8,9] . Both CMA and MA have been identified in mammals as processes important for damage and diseases of the central nervous system [10] . MA is a bulk degradation system that involves the formation of a double-membrane structure (autophagosome) that sequesters damaged organelles and proteins. The autophagosome acquires the hydrolytic enzymes necessary to degrade its cargo by fusing with lysosomes [11] . Microautophagy traps nonspecifi c cytoplasm inside vesicles via direct invagination of the lysosomal membrane. These vesicles "pinch off" into the lumen and are degraded by lysosomal hydrolases [12] .CMA is the third type of autophagy, and has so far been found only in mammalian cells [13,14] . One of its intrinsic features is the selective targeting and direct translocation into the lysosomal lumen of substrate proteins containing a targeting motif related to the pentapeptide KFERQ [15,16] [17][1...

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Interplay of LRRK2 with chaperone-mediated autophagy

Cited by 510 publications

References 55 publications

Interplay of pathogenic forms of human tau with different autophagic pathways

Interplay of pathogenic forms of human tau with different autophagic pathways

Chaperone-mediated autophagy: roles in disease and aging

Chaperone-mediated autophagy: roles in neuroprotection

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