scholarly journals Dictyostelium discoideum has a highly Q/N-rich proteome and shows an unusual resilience to protein aggregation

2015 ◽  
Vol 112 (20) ◽  
pp. E2620-E2629 ◽  
Author(s):  
Liliana Malinovska ◽  
Sandra Palm ◽  
Kimberley Gibson ◽  
Jean-Marc Verbavatz ◽  
Simon Alberti
Keyword(s):  
Dictyostelium Discoideum ◽  
Protein Misfolding ◽  
Prion Proteins ◽  
Sequence Similarity ◽  
Ubiquitin Proteasome System ◽  
Yeast Prion ◽  
Intrinsically Disordered ◽  
Exon 1 ◽  
Ubiquitin Proteasome ◽  
Misfolding Diseases

Many protein-misfolding diseases are caused by proteins carrying prion-like domains. These proteins show sequence similarity to yeast prion proteins, which can interconvert between an intrinsically disordered and an aggregated prion state. The natural presence of prions in yeast has provided important insight into disease mechanisms and cellular proteostasis. However, little is known about prions in other organisms, and it is not yet clear whether the findings in yeast can be generalized. Using bioinformatics tools, we show that Dictyostelium discoideum has the highest content of prion-like proteins of all organisms investigated to date, suggesting that its proteome has a high overall aggregation propensity. To study mechanisms regulating these proteins, we analyze the behavior of several well-characterized prion-like proteins, such as an expanded version of human huntingtin exon 1 (Q103) and the prion domain of the yeast prion protein Sup35 (NM), in D. discoideum. We find that these proteins remain soluble and are innocuous to D. discoideum, in contrast to other organisms, where they form cytotoxic cytosolic aggregates. However, when exposed to conditions that compromise molecular chaperones, these proteins aggregate and become cytotoxic. We show that the disaggregase Hsp101, a molecular chaperone of the Hsp100 family, dissolves heat-induced aggregates and promotes thermotolerance. Furthermore, prion-like proteins accumulate in the nucleus, where they are targeted by the ubiquitin–proteasome system. Our data suggest that D. discoideum has undergone specific adaptations that increase the proteostatic capacity of this organism and allow for an efficient regulation of its prion-like proteome.

scholarly journals Accumulation of Mutant Huntingtin Fragments in Aggresome-like Inclusion Bodies as a Result of Insufficient Protein Degradation

2001 ◽  
Vol 12 (5) ◽  
pp. 1393-1407 ◽  
Author(s):  
Stephanie Waelter ◽  
Annett Boeddrich ◽  
Rudi Lurz ◽  
Eberhard Scherzinger ◽  
Gerhild Lueder ◽  
...  
Keyword(s):  
Inclusion Bodies ◽  
Rna Binding ◽  
Ubiquitin Proteasome System ◽  
26S Proteasome ◽  
Therapeutic Interventions ◽  
Ultrastructural Changes ◽  
Huntingtin Protein ◽  
Fibrillar Morphology ◽  
Exon 1 ◽  
Ubiquitin Proteasome

The huntingtin exon 1 proteins with a polyglutamine repeat in the pathological range (51 or 83 glutamines), but not with a polyglutamine tract in the normal range (20 glutamines), form aggresome-like perinuclear inclusions in human 293 Tet-Off cells. These structures contain aggregated, ubiquitinated huntingtin exon 1 protein with a characteristic fibrillar morphology. Inclusion bodies with truncated huntingtin protein are formed at centrosomes and are surrounded by vimentin filaments. Inhibition of proteasome activity resulted in a twofold increase in the amount of ubiquitinated, SDS-resistant aggregates, indicating that inclusion bodies accumulate when the capacity of the ubiquitin–proteasome system to degrade aggregation-prone huntingtin protein is exhausted. Immunofluorescence and electron microscopy with immunogold labeling revealed that the 20S, 19S, and 11S subunits of the 26S proteasome, the molecular chaperones BiP/GRP78, Hsp70, and Hsp40, as well as the RNA-binding protein TIA-1, the potential chaperone 14–3-3, and α-synuclein colocalize with the perinuclear inclusions. In 293 Tet-Off cells, inclusion body formation also resulted in cell toxicity and dramatic ultrastructural changes such as indentations and disruption of the nuclear envelope. Concentration of mitochondria around the inclusions and cytoplasmic vacuolation were also observed. Together these findings support the hypothesis that the ATP-dependent ubiquitin–proteasome system is a potential target for therapeutic interventions in glutamine repeat disorders.

Degradation of mutant huntingtin via the ubiquitin/proteasome system is modulated by FE65

2012 ◽  
Vol 443 (3) ◽  
pp. 681-689 ◽  
Author(s):  
Wan Ning Vanessa Chow ◽  
Hon Wing Luk ◽  
Ho Yin Edwin Chan ◽  
Kwok-Fai Lau
Keyword(s):  
Cell Death ◽  
Degradation Mechanism ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Adaptor Protein ◽  
Ubiquitin Proteasome System ◽  
Exon 1 ◽  
Ubiquitin Proteasome

An unstable expansion of the polyglutamine repeat within exon 1 of the protein Htt (huntingtin) causes HD (Huntington's disease). Mounting evidence shows that accumulation of N-terminal mutant Htt fragments is the source of disruption of normal cellular processes which ultimately leads to neuronal cell death. Understanding the degradation mechanism of mutant Htt and improving its clearance has emerged as a new direction in developing therapeutic approaches to treat HD. In the present study we show that the brain-enriched adaptor protein FE65 is a novel interacting partner of Htt. The binding is mediated through WW–polyproline interaction and is dependent on the length of the polyglutamine tract. Interestingly, a reduction in mutant Htt protein level was observed in FE65-knockdown cells, and the process requires the UPS (ubiquitin/proteasome system). Moreover, the ubiquitination level of mutant Htt was found to be enhanced when FE65 is knocked down. Immunofluroescence staining revealed that FE65 associates with mutant Htt aggregates. Additionally, we demonstrated that overexpression of FE65 increases mutant Htt-induced cell death both in vitro and in vivo. These results suggest that FE65 facilitates the accumulation of mutant Htt in cells by preventing its degradation via the UPS, and thereby enhances the toxicity of mutant Htt.

scholarly journals Co-Transmission of Alpha-Synuclein and TPPP/p25 Inhibits Their Proteolytic Degradation in Human Cell Models

2021 ◽  
Vol 8 ◽  
Author(s):  
Attila Lehotzky ◽  
Judit Oláh ◽  
János Tibor Fekete ◽  
Tibor Szénási ◽  
Edit Szabó ◽  
...  
Keyword(s):  
Cell Types ◽  
Ubiquitin Proteasome System ◽  
Alpha Synuclein ◽  
Human Cells ◽  
Proteolytic Degradation ◽  
Intrinsically Disordered ◽  
Cell Transmission ◽  
Key Factor ◽  
Ubiquitin Proteasome ◽  
Combined Strategy

The pathological association of alpha-synuclein (SYN) and Tubulin Polymerization Promoting Protein (TPPP/p25) is a key factor in the etiology of synucleinopathies. In normal brains, the intrinsically disordered SYN and TPPP/p25 are not found together but exist separately in neurons and oligodendrocytes, respectively; in pathological states, however, they are found in both cell types due to their cell-to-cell transmission. The autophagy degradation of the accumulated/assembled SYN has been considered as a potential therapeutic target. We have shown that the hetero-association of SYN with TPPP/p25 after their uptake from the medium by human cells (which mimics cell-to-cell transmission) inhibits both their autophagy- and the ubiquitin-proteasome system-derived elimination. These results were obtained by ELISA, Western blot, FACS and immunofluorescence confocal microscopy using human recombinant proteins and living human cells; ANOVA statistical analysis confirmed that TPPP/p25 counteracts SYN degradation by hindering the autophagy maturation at the stage of LC3B-SQSTM1/p62-derived autophagosome formation and its fusion with lysosome. Recently, fragments of TPPP/p25 that bind to the interface between the two hallmark proteins have been shown to inhibit their pathological assembly. In this work, we show that the proteolytic degradation of SYN on its own is more effective than when it is complexed with TPPP/p25. The combined strategy of TPPP/p25 fragments and proteolysis may ensure prevention and/or elimination of pathological SYN assemblies.

Neurodegenerative Diseases as Protein Misfolding Disorders

2016 ◽  
Author(s):  
Tomohiro Nakamura ◽  
Stuart A. Lipton
Keyword(s):  
Quality Control ◽  
Neurodegenerative Diseases ◽  
Protein Misfolding ◽  
Protein Quality ◽  
Protein S ◽  
Ubiquitin Proteasome System ◽  
Misfolded Proteins ◽  
Redox Stress ◽  
Chemical Mechanisms ◽  
Ubiquitin Proteasome

Neurodegenerative diseases (NDDs) often represent disorders of protein folding. Rather than large aggregates, recent evidence suggests that soluble oligomers of misfolded proteins are the most neurotoxic species. Emerging evidence points to small, soluble oligomers of misfolded proteins as the cause of synaptic dysfunction and loss, the major pathological correlate to disease progression in many NDDs including Alzheimer’s disease. The protein quality control machinery of the cell, which includes molecular chaperones as found in the endoplasmic reticulum (ER), the ubiquitin-proteasome system (UPS), and various forms of autophagy, can counterbalance the accumulation of misfolded proteins to some extent. Their ability to eliminate the neurotoxic effects of misfolded proteins, however, declines with age. A plausible explanation for the age-dependent deterioration of the quality control machinery involves compromise of these systems by excessive generation of reactive oxygen species (ROS), such as superoxide anion (O2-), and reactive nitrogen species (RNS), such as nitric oxide (NO). The resulting redox stress contributes to the accumulation of misfolded proteins. Here, we focus on aberrantly increased generation of NO-related species since this process appears to accelerate the manifestation of key neuropathological features, including protein misfolding. We review the chemical mechanisms of posttranslational modification by RNS such as protein S-nitrosylation of critical cysteine thiol groups and nitration of tyrosine residues, showing how they contribute to the pathogenesis of NDDs.

The ubiquitin–proteasome system regulates the stability and activity of the glucose sensor glucokinase in pancreatic β-cells

2013 ◽  
Vol 456 (2) ◽  
pp. 173-184 ◽  
Author(s):  
Anke Hofmeister-Brix ◽  
Sigurd Lenzen ◽  
Simone Baltrusch
Keyword(s):  
Protein Misfolding ◽  
Glucose Sensor ◽  
Ubiquitin Proteasome System ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Insulin Secreting Cells ◽  
Ubiquitin Proteasome ◽  
The Stability

The glucose phosphorylating enzyme glucokinase is regulated by the ubiquitin–proteasome system. Inhibition of the proteasome leads to reduced glucokinase activity, glucokinase protein misfolding and localization of glucokinase in aggresomes in insulin-secreting cells, pancreatic β-cells and hepatocytes.

scholarly journals Proteostasis and Mitochondrial Role on Psychiatric and Neurodegenerative Disorders: Current Perspectives

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Pablo Olivero ◽  
Carlo Lozano ◽  
Ramón Sotomayor-Zárate ◽  
Nicolás Meza-Concha ◽  
Marcelo Arancibia ◽  
...  
Keyword(s):  
Neurodegenerative Disorders ◽  
Protein Misfolding ◽  
Cell Damage ◽  
Mitochondrial Dynamics ◽  
Ubiquitin Proteasome System ◽  
Compensatory Mechanisms ◽  
Mitochondrial Functions ◽  
Ubiquitin Proteasome ◽  
Psychiatric Conditions ◽  
Therapeutic Alternatives

Proteostasis involves processes that are fundamental for neural viability. Thus, protein misfolding and the formation of toxic aggregates at neural level, secondary to dysregulation of the conservative mechanisms of proteostasis, are associated with several neuropsychiatric conditions. It has been observed that impaired mitochondrial function due to a dysregulated proteostasis control system, that is, ubiquitin-proteasome system and chaperones, could also have effects on neurodegenerative disorders. We aimed to critically analyze the available findings regarding the neurobiological implications of proteostasis on the development of neurodegenerative and psychiatric diseases, considering the mitochondrial role. Proteostasis alterations in the prefrontal cortex implicate proteome instability and accumulation of misfolded proteins. Altered mitochondrial dynamics, especially in proteostasis processes, could impede the normal compensatory mechanisms against cell damage. Thereby, altered mitochondrial functions on regulatory modulation of dendritic development, neuroinflammation, and respiratory function may underlie the development of some psychiatric conditions, such as schizophrenia, being influenced by a genetic background. It is expected that with the increasing evidence about proteostasis in neuropsychiatric disorders, new therapeutic alternatives will emerge.

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

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Karina Cuanalo-Contreras ◽  
Abhisek Mukherjee ◽  
Claudio Soto
Keyword(s):  
Protein Misfolding ◽  
Current Knowledge ◽  
Ubiquitin Proteasome System ◽  
Unfolded Protein ◽  
Natural Defense ◽  
Dependent Protein ◽  
The Unfolded Protein Response ◽  
Misfolding Diseases ◽  
Protein Response

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.

scholarly journals Functional Characterisation of the Autophagy ATG12~5/16 Complex in Dictyostelium discoideum

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1179 ◽  
Author(s):  
Malte Karow ◽  
Sarah Fischer ◽  
Susanne Meßling ◽  
Roman Konertz ◽  
Jana Riehl ◽  
...  
Keyword(s):  
Dictyostelium Discoideum ◽  
Ubiquitin Proteasome System ◽  
Strong Increase ◽  
Knock Out ◽  
E Coli ◽  
Atg Proteins ◽  
Functional Characterisation ◽  
Independent Functions ◽  
Ubiquitin Proteasome ◽  
Essential Function

Macroautophagy, a highly conserved and complex intracellular degradative pathway, involves more than 20 core autophagy (ATG) proteins, among them the hexameric ATG12~5/16 complex, which is part of the essential ubiquitin-like conjugation systems in autophagy. Dictyostelium discoideum atg5 single, atg5/12 double, and atg5/12/16 triple gene knock-out mutant strains displayed similar defects in the conjugation of ATG8 to phosphatidylethanolamine, development, and cell viability upon nitrogen starvation. This implies that ATG5, 12 and 16 act as a functional unit in canonical autophagy. Macropinocytosis of TRITC dextran and phagocytosis of yeast were significantly decreased in ATG5¯ and ATG5¯/12¯ and even further in ATG5¯/12¯/16¯ cells. In contrast, plaque growth on Klebsiella aerogenes was about twice as fast for ATG5¯ and ATG5¯/12¯/16¯ cells in comparison to AX2, but strongly decreased for ATG5¯/12¯ cells. Along this line, phagocytic uptake of Escherichia coli was significantly reduced in ATG5¯/12¯ cells, while no difference in uptake, but a strong increase in membrane association of E. coli, was seen for ATG5¯ and ATG5¯/12¯/16¯ cells. Proteasomal activity was also disturbed in a complex fashion, consistent with an inhibitory activity of ATG16 in the absence of ATG5 and/or ATG12. Our results confirm the essential function of the ATG12~5/16 complex in canonical autophagy, and furthermore are consistent with autophagy-independent functions of the complex and its individual components. They also strongly support the placement of autophagy upstream of the ubiquitin-proteasome system (UPS), as a fully functional UPS depends on autophagy.

scholarly journals The Autophagy-Lysosomal Pathways and Their Emerging Roles in Modulating Proteostasis in Tumors

Cells ◽  
2018 ◽  
Vol 8 (1) ◽  
pp. 4 ◽  
Author(s):  
Zhen Dong ◽  
Hongjuan Cui
Keyword(s):  
Protein Misfolding ◽  
Tumor Development ◽  
Ubiquitin Proteasome System ◽  
Tumor Treatment ◽  
Unfolded Protein ◽  
Normal Physiological Condition ◽  
Ubiquitin Proteasome ◽  
The Alps ◽  
Protein Response ◽  
Chaperone Mediated Autophagy

In normal physiological condition, the maintenance of cellular proteostasis is a prerequisite for cell growth, functioning, adapting to changing micro-environments, and responding to extracellular stress. Cellular proteostasis is maintained by specific proteostasis networks (PNs) to prevent protein misfolding, aggregating, and accumulating in subcellular compartments. Commonly, the PNs are composed of protein synthesis, molecular chaperones, endoplasmic reticulum (ER), unfolded protein response (UPR), stress response pathways (SRPs), secretions, ubiquitin proteasome system (UPS), and autophagy-lysosomal pathways (ALPs). Although great efforts have been made to explore the underlying detailed mechanisms of proteostasis, there are many questions remain to explore, especially in proteostasis regulated by the ALPs. Proteostasis out-off-balance is correlated with various human diseases such as diabetes, stroke, inflammation, hypertension, pulmonary fibrosis, and Alzheimer’s disease. , enhanced regulation of PNs is observed in tumors, thereby indicating that proteostasis may play a pivotal role in tumorigenesis and cancer development. Recently, inhibitors targeting the UPS have shown to be failed in solid tumor treatment. However, there is growing evidence showing that the ALPs play important roles in regulation of proteostasis alone or with a crosstalk with other PNs in tumors. In this review, we provide insights into the proteostatic process and how it is regulated by the ALPs, such as macroautophagy, aggrephagy, chaperone-mediated autophagy, microautophagy, as well as mitophagy during tumor development.

scholarly journals Dysregulation of the Autophagy-Endolysosomal System in Amyotrophic Lateral Sclerosis and Related Motor Neuron Diseases

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Asako Otomo ◽  
Lei Pan ◽  
Shinji Hadano
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Protein Misfolding ◽  
Disease Onset ◽  
Ubiquitin Proteasome System ◽  
Protective Role ◽  
Motor Neuron Diseases ◽  
Ubiquitin Proteasome ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a heterogeneous group of incurable motor neuron diseases (MNDs) characterized by a selective loss of upper and lower motor neurons in the brain and spinal cord. Most cases of ALS are sporadic, while approximately 5–10% cases are familial. More than 16 causative genes for ALS/MNDs have been identified and their underlying pathogenesis, including oxidative stress, endoplasmic reticulum stress, excitotoxicity, mitochondrial dysfunction, neural inflammation, protein misfolding and accumulation, dysfunctional intracellular trafficking, abnormal RNA processing, and noncell-autonomous damage, has begun to emerge. It is currently believed that a complex interplay of multiple toxicity pathways is implicated in disease onset and progression. Among such mechanisms, ones that are associated with disturbances of protein homeostasis, the ubiquitin-proteasome system and autophagy, have recently been highlighted. Although it remains to be determined whether disease-associated protein aggregates have a toxic or protective role in the pathogenesis, the formation of them results from the imbalance between generation and degradation of misfolded proteins within neuronal cells. In this paper, we focus on the autophagy-lysosomal and endocytic degradation systems and implication of their dysfunction to the pathogenesis of ALS/MNDs. The autophagy-endolysosomal pathway could be a major target for the development of therapeutic agents for ALS/MNDs.

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