An inducible chaperone adapts proteasome assembly to stress

The proteasome is essential for the selective degradation of most cellular proteins. To survive overwhelming demands on the proteasome arising during environmental stresses, cells increase proteasome abundance. Proteasome assembly is known to be complex. How stressed cells overcome this vital challenge is unknown. In an unbiased suppressor screen aimed at rescuing the defects of a yeast Rpt6 thermosensitive proteasome mutant, we identified a protein, hereafter named Adc17, as it functions as an ATPase dedicated chaperone. Adc17 interacts with the amino terminus of Rpt6 to assist formation of the Rpt6-Rpt3 ATPase pair, an early step in proteasome assembly. Adc17 is important for cell fitness, and its absence aggravates proteasome defects. The abundance of Adc17 increases upon proteasome stresses, and its function is crucial to maintain homeostatic proteasome levels. Thus, cells have mechanisms to adjust proteasome assembly when demands increase, and Adc17 is a critical effector of this process

Estudio del rol de los agregados proteicos en el envejecimiento

"El envejecimiento se define como la pérdida progresiva de la función que incrementa la vulnerabilidad a los factores ambientales, enfermedades que conducen a la muerte. La evidencia reciente sugiere que existe una acumulación de distintas proteínas insolubles durante el envejecimiento, incluso en ausencia de condiciones patológicas. La hipótesis de este trabajo consiste en que durante el envejecimiento existe una acumulación progresiva de agregados proteicos de tipo amiloide y estos juegan un rol en el proceso de envejecimiento. Para explorar lo anterior, se utilizó una batería de técnicas dirigidas a la caracterización de la agregación proteica durante el envejecimiento en distintos modelos. Los resultados indican que existe un incremento progresivo en la cantidad de proteínas insolubles, que presentan resistencia a la digestión y reactividad a anticuerpos conformacionales anti-amiloide y a la tioflavina T, lo cual sugiere que existe acumulación de agregados amiloides durante la vida. Para elucidar si la agregación proteica juega un rol en el envejecimiento, se manipuló in vivo dicho proceso utilizando inhibidores de la agregación, el tratamiento incrementó de manera significativa la vida y salud en C. elegans. En este trabajo se propone un modelo en el cual, durante el envejecimiento, distintas proteínas sufren plegamientos anómalos de tipo amiloides, lo que pudiera interferir con las funciones normales de la célula y ocasionar el fenotipo observado en el envejecimiento. En conjunto, la evidencia presentada sugiere que la acumulación de agregados amiloides es una característica conservada en el envejecimiento y que la prevención o remoción de los mismos pudiera ser una herramienta terapéutica para extender los años de vida activa y la salud.

Natural Products as Modulators of the Proteostasis Machinery: Implications in Neurodegenerative Diseases

Proteins play crucial and diverse roles within the cell. To exert their biological function they must fold to acquire an appropriate three-dimensional conformation. Once their function is fulfilled, they need to be properly degraded to hamper any possible damage. Protein homeostasis or proteostasis comprises a complex interconnected network that regulates different steps of the protein quality control, from synthesis and folding, to degradation. Due to the primary role of proteins in cellular function, the integrity of this network is critical to assure functionality and health across lifespan. Proteostasis failure has been reported in the context of aging and neurodegeneration, such as Alzheimer’s and Parkinson’s disease. Therefore, targeting the proteostasis elements emerges as a promising neuroprotective therapeutic approach to prevent or ameliorate the progression of these disorders. A variety of natural products are known to be neuroprotective by protein homeostasis interaction. In this review, we will focus on the current knowledge regarding the use of natural products as modulators of different components of the proteostasis machinery within the framework of age-associated neurodegenerative diseases

Role of Protein Misfolding and Proteostasis Deficiency in Protein Misfolding Diseases and Aging

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

Natural Products as Modulators of the Proteostasis Machinery: Implications in Neurodegenerative Diseases.

Proteins play crucial and diverse roles within the cell. To exert their biological function they must fold to acquire an appropriate three-dimensional conformation. Once their function is fulfilled, they need to be properly degraded to hamper any possible damage. Protein homeostasis or proteostasis comprises a complex interconnected network that regulates different steps of the protein quality control, from synthesis and folding, to degradation. Due to the primary role of proteins in cellular function, the integrity of this network is critical to assure functionality and health across lifespan. Proteostasis failure has been reported in the context of aging and neurodegeneration, such as Alzheimer's and Parkinson's disease. Therefore, targeting the proteostasis elements emerges as a promising neuroprotective therapeutic approach to prevent or ameliorate the progression of these disorders. A variety of natural products are known to be neuroprotective by protein homeostasis interaction. In this review, we will focus on the current knowledge regarding the use of natural products as modulators of different components of the proteostasis machinery within the framework of age-associated neurodegenerative diseases

Nrf2 mitigates LRRK2- and α-synuclein–induced neurodegeneration by modulating proteostasis

Mutations in leucine-rich repeat kinase 2 (LRRK2) and α-synuclein lead to Parkinson’s disease (PD). Disruption of protein homeostasis is an emerging theme in PD pathogenesis, making mechanisms to reduce the accumulation of misfolded proteins an attractive therapeutic strategy. We determined if activating nuclear factor erythroid 2-related factor (Nrf2), a potential therapeutic target for neurodegeneration, could reduce PD-associated neuron toxicity by modulating the protein homeostasis network. Using a longitudinal imaging platform, we visualized the metabolism and location of mutant LRRK2 and α-synuclein in living neurons at the single-cell level. Nrf2 reduced PD-associated protein toxicity by a cell-autonomous mechanism that was time-dependent. Furthermore, Nrf2 activated distinct mechanisms to handle different misfolded proteins. Nrf2 decreased steady-state levels of α-synuclein in part by increasing α-synuclein degradation. In contrast, Nrf2 sequestered misfolded diffuse LRRK2 into more insoluble and homogeneous inclusion bodies. By identifying the stress response strategies activated by Nrf2, we also highlight endogenous coping responses that might be therapeutically bolstered to treat PD