Autophagy: An Alternative Degradation Mechanism for Misfolded Proteins

Kon, Maria; Cuervo, Ana María

doi:10.1002/9780470572702.ch6

Cited by 3 publications

(3 citation statements)

References 56 publications

(89 reference statements)

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“…There is no system for degrading misfolded proteins within the confines of the ER that we know of. Rather, proteins must either be exported back into the cytoplasm for degradation by the proteasome (Werner et al 1996;Brodsky and McCracken 1997;McCracken et al 1998;McCracken and Brodsky 2003) or delivered by vesicle trafficking to the lysosome by one of several possible mechanisms (Kruse et al 2006;Kon and Cuervo 2010). Both pathways are complex and tightly regulated.…”

Section: The Proteostasis Challenges Of the Endoplasmic Reticulum Secmentioning

confidence: 99%

“…The small heat shock proteins and the NACs are examples of chaperones that partition between high-and lowaffinity states without using ATPase activity (Haslbeck et al 2005). Although it is clear that folding and degradation by the ubiquitin proteasome system and the lysosome, likely mediated by the process of autophagy, is linked to frustrated chaperone/chaperonin-mediated folding (DeMartino and Gillette 2007;Finley 2009;Kon and Cuervo 2010;Smith et al 2011), it remains to be worked out exactly how the degradation decisions are made. The degradation of aggregated and chronically misfolded proteins is critical to prevent depletion of that protein from the soluble pool and the sequestration of other functional proteins by aggregates to prevent a gain-of-toxic-function phenotype (Olzscha et al 2011), the origins of which are only partially understood.…”

Section: General Introduction To Protein Foldingmentioning

confidence: 99%

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Chemical and Biological Approaches for Adapting Proteostasis to Ameliorate Protein Misfolding and Aggregation Diseases-Progress and Prognosis

Lindquist

Kelly²

2011

Cold Spring Harbor Perspectives in Biology

171

139

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Maintaining the proteome to preserve the health of an organism in the face of developmental changes, environmental insults, infectious diseases, and rigors of aging is a formidable task. The challenge is magnified by the inheritance of mutations that render individual proteins subject to misfolding and/or aggregation. Maintenance of the proteome requires the orchestration of protein synthesis, folding, degradation, and trafficking by highly conserved/deeply integrated cellular networks. In humans, no less than 2000 genes are involved. Stress sensors detect the misfolding and aggregation of proteins in specific organelles and respond by activating stress-responsive signaling pathways. These culminate in transcriptional and posttranscriptional programs that up-regulate the homeostatic mechanisms unique to that organelle. Proteostasis is also strongly influenced by the general properties of protein folding that are intrinsic to every proteome. These include the kinetics and thermodynamics of the folding, misfolding, and aggregation of individual proteins. We examine a growing body of evidence establishing that when cellular proteostasis goes awry, it can be reestablished by deliberate chemical and biological interventions. We start with approaches that employ chemicals or biological agents to enhance the general capacity of the proteostasis network. We then introduce chemical approaches to prevent the misfolding or aggregation of specific proteins through direct binding interactions. We finish with evidence that synergy is achieved with the combination of mechanistically distinct approaches to reestablish organismal proteostasis.

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Section: The Proteostasis Challenges Of the Endoplasmic Reticulum Secmentioning

confidence: 99%

Section: General Introduction To Protein Foldingmentioning

confidence: 99%

Chemical and Biological Approaches for Adapting Proteostasis to Ameliorate Protein Misfolding and Aggregation Diseases-Progress and Prognosis

Lindquist

Kelly²

2011

Cold Spring Harbor Perspectives in Biology

171

139

View full text Add to dashboard Cite

show abstract

“…There is no mechanism for degrading nonnative proteins within the confines of the ER that we know of (Nakatsukasa and Brodsky 2008). Instead, these conformationally abnormal proteins are delivered by vesicle trafficking to the lysosome by one of several possible mechanisms (Kruse et al 2006;Kon and Cuervo 2010) or they are exported into the cytoplasm for degradation by the proteasome, in the process called ERAD (Werner et al 1996;Brodsky and McCracken 1997;McCracken et al 1998;McCracken and Brodsky 2003;Brodsky 2012).…”

Section: The Proteostasis Challenges Of the Endoplasmic Reticulum Sec...mentioning

confidence: 99%

Pharmacologic Approaches for Adapting Proteostasis in the Secretory Pathway to Ameliorate Protein Conformational Diseases

Kelly

2019

Cold Spring Harb Perspect Biol

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Maintenance of the proteome, ensuring the proper locations, proper conformations, appropriate concentrations, etc., is essential to preserve the health of an organism in the face of environmental insults, infectious diseases, and the challenges associated with aging. Maintaining the proteome is even more difficult in the background of inherited mutations that render a given protein and others handled by the same proteostasis machinery misfolding prone and/or aggregation prone. Maintenance of the proteome or maintaining proteostasis requires the orchestration of protein synthesis, folding, trafficking, and degradation by way of highly conserved, interacting, and competitive proteostasis pathways. Each subcellular compartment has a unique proteostasis network compromising common and specialized proteostasis maintenance pathways. Stress-responsive signaling pathways detect the misfolding and/or aggregation of proteins in specific subcellular compartments using stress sensors and respond by generating an active transcription factor. Subsequent transcriptional programs up-regulate proteostasis network capacity (i.e., ability to fold and degrade proteins in that compartment). Stress-responsive signaling pathways can also be linked by way of signaling cascades to nontranscriptional means to reestablish proteostasis (e.g., by translational attenuation). Proteostasis is also strongly influenced by the inherent kinetics and thermodynamics of the folding, misfolding, and aggregation of individual proteins, and these sequence-based attributes in combination with proteostasis network capacity together influence proteostasis. In this review, we will focus on the growing body of evidence that proteostasis deficits leading to human pathology can be reversed by pharmacologic adaptation of proteostasis network capacity through stress-responsive signaling pathway activation. The power of this approach will be exemplified by focusing on the ATF6 arm of the unfolded protein response stress responsive-signaling pathway that regulates proteostasis network capacity of the secretory pathway.E ukaryotic protein homeostasis, or proteostasis, is maintained by a diverse number of integrated pathways that sometimes complement each other and in other scenarios compete to regulate the function of the proteome (Mori-

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Protein Quality Control System in Neurodegeneration: A Healing Company Hard to Beat but Failure is Fatal

Chhangani

Mishra

2013

Mol Neurobiol

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A common feature in most neurodegenerative diseases and aging is the progressive accumulation of damaged proteins. Proteins are essential for all crucial biological functions. Under some notorious conditions, proteins loss their three dimensional native conformations and are converted into disordered aggregated structures. Such changes rise into pathological conditions and eventually cause serious protein conformation disorders. Protein aggregation and inclusion bodies formation mediated multifactorial proteotoxic stress has been reported in the progression of Parkinson's disease (PD), Huntington's disease (HD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and Prion disease. Ongoing studies have been remarkably informative in providing a systematic outlook for better understanding the concept and fundamentals of protein misfolding and aggregations. However, the precise role of protein quality control system and precursors of this mechanism remains elusive. In this review, we highlight recent insights and discuss emerging cytoprotective strategies of cellular protein quality control system implicated in protein deposition diseases. Our current review provides a clear, understandable framework of protein quality control system that may offer the more suitable therapeutic strategies for protein-associated diseases.

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Autophagy: An Alternative Degradation Mechanism for Misfolded Proteins

Cited by 3 publications

References 56 publications

Chemical and Biological Approaches for Adapting Proteostasis to Ameliorate Protein Misfolding and Aggregation Diseases-Progress and Prognosis

Chemical and Biological Approaches for Adapting Proteostasis to Ameliorate Protein Misfolding and Aggregation Diseases-Progress and Prognosis

Pharmacologic Approaches for Adapting Proteostasis in the Secretory Pathway to Ameliorate Protein Conformational Diseases

Protein Quality Control System in Neurodegeneration: A Healing Company Hard to Beat but Failure is Fatal

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