Chaperone-mediated autophagy prevents collapse of the neuronal metastable proteome

Bourdenx, Mathieu; Martín‐Segura, Adrián; Scrivo, Aurora; Rodríguez-Navarro, José Antonio; Kaushik, Susmita; Tasset, Inmaculada; Díaz, Antonio; Storm, Nadia; Xin, Qisheng; Juste, Yves R.; Stevenson, Erica; Luengo, Enrique; Clement, Cristina C.; Choi, Se Joon; Krogan, Nevan J.; Mosharov, Eugene V.; Santambrogio, Laura; Grueninger, Fiona; Collin, Ludovic; Swaney, Danielle L.; Sulzer, David; Gavathiotis, Evripidis; Cuervo, Ana María

doi:10.1016/j.cell.2021.03.048

Cited by 161 publications

(142 citation statements)

References 109 publications

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“…The cellular protein homeostasis systems that are regulated by autophagy and the endosome/lysosome pathways may lie at the crossroads of APP and tau metabolism. ( Bourdenx et al, 2021 ). These degradation systems play a central role in removing misfolded proteins ( Frake et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

A ß-Secretase Modulator Decreases Tau Pathology and Preserves Short-Term Memory in a Mouse Model of Neurofibrillary Degeneration

et al. 2021

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Identifying which among several in cellulo pharmacological activities is necessary for the proper in vivo activity is essential for further drug development against Alzheimer’s disease pathophysiological processes. An in-depth structure–activity relationship–based study has been carried out, and two molecules, named MAGS02-14 and PEL24-199, that share a ß-secretase modulatory effect associated or not to a lysosomotropic activity in cellulo have been identified. In terms of chemical formulas, MAGS02-14 and PEL24-199 only differ from each other by a single nitrogen atom. The study aimed to elucidate the in vivo pharmacological effects of lysosomotropic and/or the ß-secretase modulatory activity in a tau pathology mouse model. To address this question, the THY-Tau22 transgenic model of tauopathy was treated with both compounds for 6 weeks in a curative paradigm. Short-term memory, tau burden, and inflammatory processes were analyzed using orthogonal methods, and PEL24-199, but not MAGS02-14, was shown to restore the short-term memory and reduce the neurofibrillary degenerating process. These effects were associated with a reduced phosphorylation of tau, an increased phosphatase expression, and decreased astrogliosis. Our results, therefore, suggest that the lysosomotropic activity may be nonessential for the effect on tau pathology.

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Section: Introductionmentioning

confidence: 99%

A ß-Secretase Modulator Decreases Tau Pathology and Preserves Short-Term Memory in a Mouse Model of Neurofibrillary Degeneration

et al. 2021

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“…Moreover, a reduction in the proteolytic capacity of lysosomes from LAMP-2 deficient hepatocytes produced autophagy dysfunction, suggesting that LAMP-2 would be somehow necessary for a proper autophagy activity (Eskelinen et al, 2002). Finally, genetic, and pharmacological CMA blockage was not compensated by autophagy activity in neurons (Bourdenx et al, 2021), in mouse embryonic fibroblasts (Eskelinen et al, 2004), or 661W cells (Rodríguez-Muela et al, 2013).…”

Section: Compensation Between Chaperone-mediated Autophagy and Autophagymentioning

confidence: 98%

“…In summary, the age-related malfunction of protein quality control systems favors the accumulation of oxidized and/or polyubiquitinated proteins and increases cell vulnerability. This aspect is especially relevant in non-dividing cells such as neurons as it has been recently demonstrated (Bourdenx et al, 2021).…”

Section: The Autophagy-lysosomal Systemmentioning

confidence: 99%

Proteostasis Dysfunction in Aged Mammalian Cells. The Stressful Role of Inflammation

Ruano

2021

Front. Mol. Biosci.

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Aging is a biological and multifactorial process characterized by a progressive and irreversible deterioration of the physiological functions leading to a progressive increase in morbidity. In the next decades, the world population is expected to reach ten billion, and globally, elderly people over 80 are projected to triple in 2050. Consequently, it is also expected an increase in the incidence of age-related pathologies such as cancer, diabetes, or neurodegenerative disorders. Disturbance of cellular protein homeostasis (proteostasis) is a hallmark of normal aging that increases cell vulnerability and might be involved in the etiology of several age-related diseases. This review will focus on the molecular alterations occurring during normal aging in the most relevant protein quality control systems such as molecular chaperones, the UPS, and the ALS. Also, alterations in their functional cooperation will be analyzed. Finally, the role of inflammation, as a synergistic negative factor of the protein quality control systems during normal aging, will also be addressed. A better comprehension of the age-dependent modifications affecting the cellular proteostasis, as well as the knowledge of the mechanisms underlying these alterations, might be very helpful to identify relevant risk factors that could be responsible for or contribute to cell deterioration, a fundamental question still pending in biomedicine.

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“…Target proteins of CMA include aggregates showing a specific degradation signal, the KFERQ sequence and substrates generated by posttranslational modifications. These substrates may be entrusted to the CMA-mediated degradation system in lysosomes by interaction of the chaperone (mainly Hsp70 family) with the lysosome membrane molecule LAMP2A [218].…”

Section: Protein Quality Controlmentioning

confidence: 99%

“…After the accumulation of non-degradable autophagic cargoes, the chaperone molecules residing in the ER and participating in this signaling chain are arginylated and, via the N-terminal arginine residue, bind to the ZZ domain of p62 in the cytosol. Once bound, p62 undergoes a conformational modification that induces its polymerization and the interaction with LC3-II, a molecule anchored on the membrane of autophagosomes [218]. The autophagosome thus begins its load and, once completed, fuses with the lysosome to form the autolysosome, for the degradation by lysosomal hydrolases of both, load and p62.…”

Section: Protein Quality Controlmentioning

confidence: 99%

Protein Aggregation Landscape in Neurodegenerative Diseases: Clinical Relevance and Future Applications

Candelise

Scaricamazza

Salvatori

et al. 2021

IJMS

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Intrinsic disorder is a natural feature of polypeptide chains, resulting in the lack of a defined three-dimensional structure. Conformational changes in intrinsically disordered regions of a protein lead to unstable β-sheet enriched intermediates, which are stabilized by intermolecular interactions with other β-sheet enriched molecules, producing stable proteinaceous aggregates. Upon misfolding, several pathways may be undertaken depending on the composition of the amino acidic string and the surrounding environment, leading to different structures. Accumulating evidence is suggesting that the conformational state of a protein may initiate signalling pathways involved both in pathology and physiology. In this review, we will summarize the heterogeneity of structures that are produced from intrinsically disordered protein domains and highlight the routes that lead to the formation of physiological liquid droplets as well as pathogenic aggregates. The most common proteins found in aggregates in neurodegenerative diseases and their structural variability will be addressed. We will further evaluate the clinical relevance and future applications of the study of the structural heterogeneity of protein aggregates, which may aid the understanding of the phenotypic diversity observed in neurodegenerative disorders.

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Chaperone-mediated autophagy prevents collapse of the neuronal metastable proteome

Cited by 161 publications

References 109 publications

A ß-Secretase Modulator Decreases Tau Pathology and Preserves Short-Term Memory in a Mouse Model of Neurofibrillary Degeneration

A ß-Secretase Modulator Decreases Tau Pathology and Preserves Short-Term Memory in a Mouse Model of Neurofibrillary Degeneration

Proteostasis Dysfunction in Aged Mammalian Cells. The Stressful Role of Inflammation

Protein Aggregation Landscape in Neurodegenerative Diseases: Clinical Relevance and Future Applications

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