Responses to Muscular Exercise, Heat Shock Proteins as Regulators of Inflammation, and Mitochondrial Quality Control

Alzheimer’s Disease is driven by protein aggregation and is characterized by accumulation of Tau protein into neurofibrillary tangles. In healthy neurons the cellular protein quality control is successfully in charge of protein folding, which raises the question to which extent this control is disturbed in disease. Here, we describe that brain cells in Alzheimer’s Disease show very specific derailment of the protein quality control network. We performed a meta-analysis on the Alzheimer’s Disease Proteome database, which provides a quantitative assessment of disease-related proteome changes in six brain regions in comparison to age-matched controls. We noted that levels of all paralogs of the conserved Hsp90 chaperone family are reduced, while most other chaperones – or their regulatory co-chaperones - do not change in disease. The notable exception is a select group consisting of the stress inducible HSP70, its nucleotide exchange factor BAG3 – which links the Hsp70 system to autophagy - and neuronal small heat shock proteins, which are upregulated in disease. They are all members of a cascade controlled in the stress response, channeling proteins towards a pathway of chaperone assisted selective autophagy. Together, our analysis reveals that in an Alzheimer’s brain, with exception of Hsp90, the players of the protein quality control are still present in full strength, even in brain regions most severely affected in disease. The specific upregulation of small heat shock proteins and HSP70:BAG3, ubiquitous in all brain areas analyzed, may represent a last, unsuccessful attempt to advert cell death.

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Heat Shock Proteins and Protein Quality Control in Alzheimer’s Disease

The Molecular and Cellular Basis of Neurodegenerative Diseases ◽

10.1016/b978-0-12-811304-2.00010-9 ◽

2018 ◽

pp. 269-298 ◽

Cited By ~ 3

Author(s):

Fred W. van Leeuwen ◽

Harm H. Kampinga

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Quality Control ◽

Heat Shock ◽

Heat Shock Proteins ◽

Protein Quality ◽

Protein Quality Control ◽

Shock Proteins

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Alzheimer cells on their way to derailment show selective changes in protein quality control network

10.1101/2020.05.17.099465 ◽

2020 ◽

Cited By ~ 1

Author(s):

Margreet B. Koopman ◽

Stefan G.D Rüdiger

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Quality Control ◽

Heat Shock ◽

Heat Shock Proteins ◽

Protein Quality ◽

Protein Quality Control ◽

Brain Regions ◽

Control Network ◽

Shock Proteins

Alzheimer’s Disease is driven by protein aggregation and is characterised by accumulation of Tau protein into neurofibrillary tangles. In healthy neurons the cellular protein quality control is successfully in charge of protein folding, which raises the question to which extent this control is disturbed in disease. Here we describe that brain cells in Alzheimer’s Disease show very specific derailment of the protein quality control network. We performed a meta-analysis on the Alzheimer’s Disease Proteasome database, which provides a quantitative assessment of disease-related proteome changes in six brain regions in comparison with age-matched controls. We noted that levels of all paralogues of the conserved Hsp90 chaperone family are reduced, while most other chaperones – or their regulatory co-chaperones – do not change in disease. The notable exception is a select group consisting of the stress inducible HSP70, its nucleotide exchange factor BAG3 – which links the Hsp70 system to autophagy – and neuronal small heat shock proteins, which are upregulated in disease. They are all members of a cascade controlled in the stress response, channelling proteins towards a pathway of chaperone assisted selective autophagy. Together, our analysis reveals that in an Alzheimer’s brain, with exception of Hsp90, the players of the protein quality control are still present in full strength, even in brain regions most severely affected in disease. The specific upregulation of small heat shock proteins and HSP70:BAG3, ubiquitous in all brain areas analysed, may represent a last, unsuccessful attempt to advert neuronal cell death.

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The role of heat shock proteins and co-chaperones in heart failure

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2016.0530 ◽

2017 ◽

Vol 373 (1738) ◽

pp. 20160530 ◽

Cited By ~ 27

Author(s):

Mark J. Ranek ◽

Marisa J. Stachowski ◽

Jonathan A. Kirk ◽

Monte S. Willis

Keyword(s):

Heart Failure ◽

Quality Control ◽

Heat Shock ◽

Heat Shock Proteins ◽

Structural Integrity ◽

Protein Quality ◽

Protein Quality Control ◽

Experimental Models ◽

Human Heart Failure ◽

Shock Proteins

The ongoing contractile and metabolic demands of the heart require a tight control over protein quality control, including the maintenance of protein folding, turnover and synthesis. In heart disease, increases in mechanical and oxidative stresses, post-translational modifications (e.g., phosphorylation), for example, decrease protein stability to favour misfolding in myocardial infarction, heart failure or ageing. These misfolded proteins are toxic to cardiomyocytes, directly contributing to the common accumulation found in human heart failure. One of the critical class of proteins involved in protecting the heart against these threats are molecular chaperones, including the heat shock protein70 (HSP70), HSP90 and co-chaperones CHIP (carboxy terminus of Hsp70-interacting protein, encoded by the Stub1 gene) and BAG-3 (BCL2-associated athanogene 3). Here, we review their emerging roles in the maintenance of cardiomyocytes in human and experimental models of heart failure, including their roles in facilitating the removal of misfolded and degraded proteins, inhibiting apoptosis and maintaining the structural integrity of the sarcomere and regulation of nuclear receptors. Furthermore, we discuss emerging evidence of increased expression of extracellular HSP70, HSP90 and BAG-3 in heart failure, with complementary independent roles from intracellular functions with important therapeutic and diagnostic considerations. While our understanding of these major HSPs in heart failure is incomplete, there is a clear potential role for therapeutic modulation of HSPs in heart failure with important contextual considerations to counteract the imbalance of protein damage and endogenous protein quality control systems. This article is part of the theme issue ‘Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective’.

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Heat Shock Proteins: Cell Protection through Protein Triage

The Scientific World JOURNAL ◽

10.1100/tsw.2010.152 ◽

2010 ◽

Vol 10 ◽

pp. 1543-1552 ◽

Cited By ~ 119

Author(s):

David Lanneau ◽

Guillaume Wettstein ◽

Philippe Bonniaud ◽

Carmen Garrido

Keyword(s):

Quality Control ◽

Heat Shock ◽

Heat Shock Proteins ◽

Protein Quality ◽

Ubiquitin Proteasome System ◽

Control Mechanisms ◽

Cell Protection ◽

Ubiquitin Proteasome ◽

Folded Proteins ◽

Shock Proteins

Heat shock proteins (HSPs) are chaperones that catalyze the proper folding of nascent proteins and the refolding of denatured proteins. The ubiquitin-proteasome system is an error-checking system that directs improperly folded proteins for destruction. A coordinated interaction between the HSPs (renaturation) and the proteasome (degradation) must exist to assure protein quality control mechanisms. Although it still remains unknown how the decision of folding vs. degradation is taken, many pieces of evidence demonstrate that HSPs interact directly or indirectly with the proteasome, assuring quite selectively the proteasomal degradation of certain proteins under stress conditions. In this review, we will describe the different data that demonstrate a role for HSP90, HSP70, HSP27, and alpha-B-crystallin in the partitioning of proteins to either one of these pathways, referred as protein triage.

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Chaperone families and interactions in metazoa

Essays in Biochemistry ◽

10.1042/ebc20160004 ◽

2016 ◽

Vol 60 (2) ◽

pp. 237-253 ◽

Cited By ~ 18

Author(s):

Yael Bar-Lavan ◽

Netta Shemesh ◽

Anat Ben-Zvi

Keyword(s):

Gene Expression ◽

Quality Control ◽

Protein Folding ◽

Heat Shock ◽

Heat Shock Proteins ◽

Heat Shock Protein ◽

Molecular Chaperones ◽

Diverse Group ◽

Acute Effects ◽

Shock Proteins

Quality control is an essential aspect of cellular function, with protein folding quality control being carried out by molecular chaperones, a diverse group of highly conserved proteins that specifically identify misfolded conformations. Molecular chaperones are thus required to support proteins affected by expressed polymorphisms, mutations, intrinsic errors in gene expression, chronic insult or the acute effects of the environment, all of which contribute to a flux of metastable proteins. In this article, we review the four main chaperone families in metazoans, namely Hsp60 (where Hsp is heat-shock protein), Hsp70, Hsp90 and sHsps (small heat-shock proteins), as well as their co-chaperones. Specifically, we consider the structural and functional characteristics of each family and discuss current models that attempt to explain how chaperones recognize and act together to protect or recover aberrant proteins.

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