Shape matters: the complex relationship between aggregation and toxicity in protein-misfolding diseases

2016 ◽  
Vol 60 (2) ◽  
pp. 181-190 ◽  
Author(s):  
Heidrun Maja Ries ◽  
Carmen Nussbaum-Krammer
Keyword(s):  
Protein Misfolding ◽  
Protein Quality ◽  
Cellular Protein ◽  
Exact Nature ◽  
High Tendency ◽  
Protein Deposits ◽  
Cellular Environment ◽  
Individual Interaction ◽  
Protein Quality Control System ◽  
Misfolding Diseases

A particular subgroup of protein-misfolding diseases, comprising Alzheimer's and Parkinson's disease, involves amyloidogenic proteins that can form alternative pathogenic conformations with a high tendency to self-assemble into oligomeric and fibrillar species. Although misfolded proteins have been clearly linked to disease, the exact nature of the toxic species remains highly controversial. Increasing evidence suggests that there is little correlation between the occurrence of macroscopic protein deposits and toxic phenotypes in affected cells and tissues. In this article, we recap amyloid aggregation pathways, describe prion-like propagation, elaborate on detrimental interactions of protein aggregates with the cellular protein quality control system and discuss why some aggregates are toxic, whereas others seem to be beneficial. On the basis of recent studies on prion strains, we reason that the specific aggregate conformation and the resulting individual interaction with the cellular environment might be the major determinant of toxicity.

scholarly journals Mechanistic Insights into the Role of Molecular Chaperones in Protein Misfolding Diseases: From Molecular Recognition to Amyloid Disassembly

2020 ◽  
Vol 21 (23) ◽  
pp. 9186
Author(s):  
Rubén Hervás ◽  
Javier Oroz
Keyword(s):  
Molecular Chaperones ◽  
Protein Misfolding ◽  
Cell Damage ◽  
Protective Role ◽  
Soluble Proteins ◽  
Protein Deposits ◽  
Client Proteins ◽  
Recognition Motifs ◽  
Misfolding Diseases

Age-dependent alterations in the proteostasis network are crucial in the progress of prevalent neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, or amyotrophic lateral sclerosis, which are characterized by the presence of insoluble protein deposits in degenerating neurons. Because molecular chaperones deter misfolded protein aggregation, regulate functional phase separation, and even dissolve noxious aggregates, they are considered major sentinels impeding the molecular processes that lead to cell damage in the course of these diseases. Indeed, members of the chaperome, such as molecular chaperones and co-chaperones, are increasingly recognized as therapeutic targets for the development of treatments against degenerative proteinopathies. Chaperones must recognize diverse toxic clients of different orders (soluble proteins, biomolecular condensates, organized protein aggregates). It is therefore critical to understand the basis of the selective chaperone recognition to discern the mechanisms of action of chaperones in protein conformational diseases. This review aimed to define the selective interplay between chaperones and toxic client proteins and the basis for the protective role of these interactions. The presence and availability of chaperone recognition motifs in soluble proteins and in insoluble aggregates, both functional and pathogenic, are discussed. Finally, the formation of aberrant (pro-toxic) chaperone complexes will also be disclosed.

scholarly journals The Crystal Structure of Archaeal Nascent Polypeptide-associated Complex (NAC) Reveals a Unique Fold and the Presence of a Ubiquitin-associated Domain

2005 ◽  
Vol 280 (16) ◽  
pp. 15849-15854 ◽  
Author(s):  
Thomas Spreter ◽  
Markus Pech ◽  
Birgitta Beatrix
Keyword(s):  
Crystal Structure ◽  
Protein Quality ◽  
Structural Features ◽  
Cellular Protein ◽  
Nascent Polypeptide ◽  
Nascent Chain ◽  
Ubiquitination Pathway ◽  
Protein Quality Control System ◽  
Cytosolic Factor ◽  
Cytosolic Factors

Nascent polypeptide-associated complex (NAC) was identified in eukaryotes as the first cytosolic factor that contacts the nascent polypeptide chain emerging from the ribosome. NAC is highly conserved from yeast to humans. Mutations in NAC cause severe embryonically lethal phenotypes in mice,Drosophila,andCaenorhabditis elegans.NAC was suggested to protect the nascent chain from inappropriate early interactions with cytosolic factors. Eukaryotic NAC is a heterodimer with two subunits sharing substantial homology with each other. All sequenced archaebacterial genomes exhibit only one gene homologous to the NAC subunits. Here we present the first archaebacterial NAC homolog. It forms a homodimer, and as eukaryotic NAC it is associated with ribosomes and contacts the emerging nascent chain on the ribosome. We present the first crystal structure of a NAC protein revealing two structural features: (i) a novel unique protein fold that mediates dimerization of the complex, and (ii) a ubiquitin-associated domain that suggests a yet unidentified role for NAC in the cellular protein quality control system via the ubiquitination pathway. Based on the presented structure we propose a model for the eukaryotic heterodimeric NAC domain.

scholarly journals Truncation-Driven Lateral Association of α-Synuclein Hinders Amyloid Clearance by the Hsp70-based Disaggregase

2021 ◽  
Vol 22 (23) ◽  
pp. 12983
Author(s):  
Aitor Franco ◽  
Jorge Cuéllar ◽  
José Ángel Fernández-Higuero ◽  
Igor de la Arada ◽  
Natalia Orozco ◽  
...  
Keyword(s):  
Neurodegenerative Disorders ◽  
Protein Quality ◽  
Mechanical Action ◽  
Cellular Protein ◽  
Type B ◽  
Post Translational Modifications ◽  
Lateral Association ◽  
N Terminus ◽  
Protein Quality Control System

The aggregation of α-synuclein is the hallmark of a collective of neurodegenerative disorders known as synucleinopathies. The tendency to aggregate of this protein, the toxicity of its aggregation intermediates and the ability of the cellular protein quality control system to clear these intermediates seems to be regulated, among other factors, by post-translational modifications (PTMs). Among these modifications, we consider herein proteolysis at both the N- and C-terminal regions of α-synuclein as a factor that could modulate disassembly of toxic amyloids by the human disaggregase, a combination of the chaperones Hsc70, DnaJB1 and Apg2. We find that, in contrast to aggregates of the protein lacking the N-terminus, which can be solubilized as efficiently as those of the WT protein, the deletion of the C-terminal domain, either in a recombinant context or as a consequence of calpain treatment, impaired Hsc70-mediated amyloid disassembly. Progressive removal of the negative charges at the C-terminal region induces lateral association of fibrils and type B* oligomers, precluding chaperone action. We propose that truncation-driven aggregate clumping impairs the mechanical action of chaperones, which includes fast protofilament unzipping coupled to depolymerization. Inhibition of the chaperone-mediated clearance of C-truncated species could explain their exacerbated toxicity and higher propensity to deposit found in vivo.

scholarly journals Oxidative stress-induced parkin misfolding, aggregation, and toxicity

2020 ◽  
Author(s):  
Martin Duennwald ◽  
Gary S. Shaw ◽  
Mohammad A. Esmaeili ◽  
Jane R. Rylett ◽  
Susanne Schmid ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Disulfide Bonds ◽  
Protein Misfolding ◽  
Protein Quality ◽  
Normal Growth ◽  
Growth Conditions ◽  
Cellular Protein ◽  
Loss Of Function ◽  
Underlying Mechanisms

Abstract Background: Excess oxidative stress and protein misfolding are major hallmarks of neurodegenerative disease, including Parkinson’s disease (PD). Mutations in the genes encoding the ubiquitin ligase parkin cause autosomal recessive juvenile forms of Parkinsonism by the loss of parkin function in mitochondrial homeostasis and cellular protein quality control, generally. Dysfunction of parkin might also contribute to sporadic forms of PD, yet the underlying mechanisms remain mostly unexplored. Methods: We obtained key results from studies in human PD brains, a mouse model, yeast, cultured neuronal cells, and in vitro biochemistry. Human postmortem Medial Temporal Gyrus tissue was fixed for immunohistochemistry. We performed biochemical analyses of protein lysates from human brain, mouse brain, yeast and cells to assess parkin modification by oxidative stress under normal growth conditions and more so under oxidative stress. Results: Our results reveal that oxidative stress damages parkin by inducing the formation of aberrant intra- and inter-molecular disulfide bonds, leading to parkin misfolding and inclusion formation, which is toxic to cells. We furthermore find that parkin is most severely oxidized in its active conformation. Conclusion: Collectively, our study identifies a mechanism by which protein oxidation can contribute to neurodegeneration in PD by combining loss of function with toxic gain of function mechanisms.

scholarly journals Predicting aggregation-prone sequences in proteins

2014 ◽  
Vol 56 ◽  
pp. 41-52 ◽  
Author(s):  
Greet De Baets ◽  
Joost Schymkowitz ◽  
Frederic Rousseau
Keyword(s):  
Protein Quality ◽  
Amino Acid Sequences ◽  
Net Charge ◽  
Diverse Range ◽  
High Tendency ◽  
Practical Applications ◽  
Aggregation Propensity ◽  
Polypeptide Sequence ◽  
Protein Quality Control System ◽  
Aggregation Tendency

Owing to its association with a diverse range of human diseases, the determinants of protein aggregation are studied intensively. It is generally accepted that the effective aggregation tendency of a protein depends on many factors such as folding efficiency towards the native state, thermodynamic stability of that conformation, intrinsic aggregation propensity of the polypeptide sequence and its ability to be recognized by the protein quality control system. The intrinsic aggregation propensity of a polypeptide sequence is related to the presence of short APRs (aggregation-prone regions) that self-associate to form intermolecular β-structured assemblies. These are typically short sequence segments (5–15 amino acids) that display high hydrophobicity, low net charge and a high tendency to form β-structures. As the presence of such APRs is a prerequisite for aggregation, a plethora of methods have been developed to identify APRs in amino acid sequences. In the present chapter, the methodological basis of these approaches is discussed, as well as some practical applications.

scholarly journals Proteostasis Failure in Neurodegenerative Diseases: Focus on Oxidative Stress

2020 ◽  
Vol 2020 ◽  
pp. 1-21 ◽  
Author(s):  
Annika Höhn ◽  
Antonella Tramutola ◽  
Roberta Cascella
Keyword(s):  
Oxidative Stress ◽  
Neurodegenerative Diseases ◽  
Protein Misfolding ◽  
Protein Quality ◽  
Cellular Protein ◽  
Protein Levels ◽  
A Cell ◽  
Lysosomal System ◽  
Turn Over ◽  
Protein Dysfunction

Protein homeostasis or proteostasis is an essential balance of cellular protein levels mediated through an extensive network of biochemical pathways that regulate different steps of the protein quality control, from the synthesis to the degradation. All proteins in a cell continuously turn over, contributing to development, differentiation, and aging. Due to the multiple interactions and connections of proteostasis pathways, exposure to stress conditions may cause various types of protein damage, altering cellular homeostasis and disrupting the entire network with additional cellular stress. Furthermore, protein misfolding and/or alterations during protein synthesis results in inactive or toxic proteins, which may overload the degradation mechanisms. The maintenance of a balanced proteome, preventing the formation of impaired proteins, is accomplished by two major catabolic routes: the ubiquitin proteasomal system (UPS) and the autophagy-lysosomal system. The proteostasis network is particularly important in nondividing, long-lived cells, such as neurons, as its failure is implicated with the development of neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. These neurological disorders share common risk factors such as aging, oxidative stress, environmental stress, and protein dysfunction, all of which alter cellular proteostasis, suggesting that general mechanisms controlling proteostasis may underlay the etiology of these diseases. In this review, we describe the major pathways of cellular proteostasis and discuss how their disruption contributes to the onset and progression of neurodegenerative diseases, focusing on the role of oxidative stress.

scholarly journals Modulating protein quality control

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Lars Plate ◽  
Ryan J Paxman ◽  
R Luke Wiseman ◽  
Jeffery W Kelly
Keyword(s):  
Quality Control ◽  
Small Molecules ◽  
Unfolded Protein Response ◽  
Protein Misfolding ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Misfolding Diseases ◽  
Protein Response

Small molecules that modulate the unfolded protein response have the potential to treat a variety of human protein misfolding diseases.

scholarly journals Western Faculty Profile: Dr. Martin L. Duennwald

2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Soojie Hong
Keyword(s):  
Quality Control ◽  
Amyotrophic Lateral Sclerosis ◽  
Protein Misfolding ◽  
Protein Quality ◽  
Assistant Professor ◽  
Cellular Protein ◽  
Independent Research ◽  
Biomedical Research Institute ◽  
Control Protein ◽  
Lateral Sclerosis

Dr. Martin L. Duennwald is a researcher and assistant professor at Western University. After conducting independent research at the Boston Biomedical Research Institute, he came to Western University in 2012 where he started the Duennwald Lab. His lab focuses on cellular protein quality control, protein misfolding and their pathological consequences in neurodegenerative diseases such as Huntington’s disease, Parkinson’s disease, and Amyotrophic Lateral Sclerosis (ALS).

scholarly journals Disrupted structure and aberrant function of CHIP mediates the loss of motor and cognitive function in preclinical models of cerebellar CHIPopathy

2018 ◽  
Author(s):  
Chang-he Shi ◽  
Carrie Rubel ◽  
Sarah E. Soss ◽  
Rebekah Sanchez-Hodge ◽  
Shuo Zhang ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Protein Quality ◽  
Cellular Protein ◽  
Active Member ◽  
Preclinical Models ◽  
Interacting Protein ◽  
Chaperone Function ◽  
On Chip ◽  
Protein Quality Control System ◽  
Ligase Function

AbstractCHIP (carboxyl terminus of heat shock 70-interacting protein) has long been recognized as an active member of the cellular protein quality control system given the ability of CHIP to function as both a co-chaperone and ubiquitin ligase. Mutations in CHIP are the driver of spinocerebellar autosomal recessive 16 (SCAR16), or cerebellar CHIPopathy, as we initially discovered this disease was caused by a loss of CHIP ubiquitin ligase function. The initial mutation describing SCAR16 was a missense mutation in the ubiquitin ligase domain of CHIP (p.T246M). Using multiple biophysical and cellular approaches, we demonstrate that T246M mutation results in structural disorganization and misfolding of the CHIP U-box domain, promoting oligomerization, and increased proteasome-dependent turnover. CHIP-T246M has no ligase activity, but maintains interactions with chaperones and alters the co-chaperone function of CHIP. To establish preclinical models of SCAR16, we engineered T246M at the endogenous locus in both mice and rats. Animals homozygous for T246M had both cognitive and motor cerebellar dysfunction distinct from those observed in the CHIP null animal model, as well as deficits in learning and memory, reflective of the cognitive deficits reported in SCAR16 patients. We conclude that the T246M mutation is not equivalent to the total loss of CHIP, supporting the concept that disease-causing CHIP mutations have different biophysical and functional repercussions on CHIP function that may directly correlate to the spectrum of clinical phenotypes observed in SCAR16 patients. Our findings both further expand our basic understanding of CHIP biology and provide meaningful mechanistic insight underlying the molecular drivers of SCAR16 disease pathology, which may be used to inform the development of novel therapeutics for this devastating disease.

scholarly journals Chemical Chaperone and Inhibitor Discovery: Potential Treatments for Protein Conformational Diseases

2007 ◽  
Vol 1 ◽  
pp. PMC.S212 ◽  
Author(s):  
Jian-Hua Zhao ◽  
Hsuan-Liang Liu ◽  
Hsin-Yi Lin ◽  
Chih-Hung Huang ◽  
Hsu-Wei Fang ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Protein Misfolding ◽  
Protein Quality ◽  
Amyloid Formation ◽  
Loss Of Function ◽  
Chemical Chaperone ◽  
Conformational Diseases ◽  
Chemical Chaperones ◽  
Theoretical Approaches ◽  
Protein Quality Control System

Protein misfolding and aggregation cause a large number of neurodegenerative diseases in humans due to (i) gain of function as observed in Alzheimer's disease, Huntington's disease, Parkinson's disease, and Prion's disease or (ii) loss of function as observed in cystic fibrosis and α1-antitrypsin deficiency. These misfolded proteins could either lead to the formation of harmful amyloids that become toxic for the cells or to be recognized and prematurely degraded by the protein quality control system. An increasing number of studies has indicated that some low-molecular-weight compounds named as chemical chaperones can reverse the mislocalization and/or aggregation of proteins associated with human conformational diseases. These small molecules are thought to non-selectively stabilize proteins and facilitate their folding. In this review, we summarize the probable mechanisms of protein conformational diseases in humans and the use of chemical chaperones and inhibitors as potential therapeutic agents against these diseases. Furthermore, recent advanced experimental and theoretical approaches underlying the detailed mechanisms of protein conformational changes and current structure-based drug designs towards protein conformational diseases are also discussed. It is believed that a better understanding of the mechanisms of conformational changes as well as the biological functions of these proteins will lead to the development and design of potential interfering compounds against amyloid formation associated with protein conformational diseases.

Sign in / Sign up

Export Citation Format

Share Document