scholarly journals Escalating protein supersaturation underlies inclusion formation in muscle proteinopathies

2019 ◽  
Author(s):  
Prajwal Ciryam ◽  
Matthew Antalek ◽  
Fernando Cid ◽  
Gian Gaetano Tartaglia ◽  
Christopher M. Dobson ◽  
...  
Keyword(s):  
Protein Misfolding ◽  
Selective Vulnerability ◽  
Aggregate Formation ◽  
Protein Aggregate ◽  
Aggregation Propensity ◽  
Inclusion Formation ◽  
Neuronal Protein ◽  
Quantitative Studies ◽  
Conformational Disorders ◽  
Protein Aggregate Myopathy

AbstractAbundant, aggregation prone or “supersaturated” proteins are a feature of neurodegeneration. Whether the principle of supersaturation can similarly explain the widespread aggregation that occurs in non-neuronal protein conformational disorders and underlies pathogenic protein aggregate formation is not established. To test this prediction we analyzed proteomic datasets of biopsies from genetic and acquired protein aggregate myopathy (PAM) patients by quantifying the changes in composition, concentration and aggregation propensity of proteins in the fibers containing inclusions and those surrounding them. We found that similar to neurodegeneration, a supersaturated subproteome of aggregate prone proteins is present in skeletal muscle from healthy patients. This subproteome escalates in degree of supersaturation as proteomic samples are taken more proximal to the pathologic inclusion, eventually exceeding its solubility limits and aggregating. While most supersaturated proteins decrease or maintain steady abundance across healthy fibers and inclusion containing fibers, supersaturated proteins within the aggregate subproteome rise in abundance, suggesting they escape normal regulation. We show in the context of a human conformational disorder that the level of supersaturation of a metastable subproteome helps to explain widespread aggregation and correlates with the histopathological state of the tissue.SignificanceIncreasing evidence implicates the phenomenon of protein supersaturation with the selective vulnerability of specific cells to protein misfolding disorders. Quantitative studies of this phenomenon, however, have only been possible post mortem in the case of neurodegenerative diseases. To overcome this limitation, we study here protein aggregate myopathies (PAMs), for which we were able to carry out systematic single fiber proteomic studies on patient-derived samples. We found not only that proteins associated with PAM inclusions are highly supersaturated in muscle but also that their supersaturation levels increases further in affected fibers. These results provide a clear illustration of how an escalation in supersaturation leads protein inclusions in vulnerable cells.

scholarly journals A metastable subproteome underlies inclusion formation in muscle proteinopathies

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Prajwal Ciryam ◽  
Matthew Antalek ◽  
Fernando Cid ◽  
Gian Gaetano Tartaglia ◽  
Christopher M. Dobson ◽  
...  
Keyword(s):  
Neurodegenerative Disorders ◽  
Pathological Feature ◽  
Protein Aggregate ◽  
Conformational Disorder ◽  
Aggregation Propensity ◽  
Inclusion Formation ◽  
Neuronal Protein ◽  
Conformational Disorders ◽  
The Brain ◽  
Protein Aggregate Myopathy

AbstractProtein aggregation is a pathological feature of neurodegenerative disorders. We previously demonstrated that protein inclusions in the brain are composed of supersaturated proteins, which are abundant and aggregation-prone, and form a metastable subproteome. It is not yet clear, however, whether this phenomenon is also associated with non-neuronal protein conformational disorders. To respond to this question, we analyzed proteomic datasets from biopsies of patients with genetic and acquired protein aggregate myopathy (PAM) by quantifying the changes in composition, concentration and aggregation propensity of proteins in the fibers containing inclusions and those surrounding them. We found that a metastable subproteome is present in skeletal muscle from healthy patients. The expression of this subproteome escalate as proteomic samples are taken more proximal to the pathologic inclusion, eventually exceeding its solubility limits and aggregating. While most supersaturated proteins decrease or maintain steady abundance across healthy fibers and inclusion-containing fibers, proteins within the metastable subproteome rise in abundance, suggesting that they escape regulation. Taken together, our results show in the context of a human conformational disorder that the supersaturation of a metastable subproteome underlies widespread aggregation and correlates with the histopathological state of the tissue.

scholarly journals TDP-43 aggregation inside micronuclei reveals a potential mechanism for protein inclusion formation in ALS

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Cristian A. Droppelmann ◽  
Danae Campos-Melo ◽  
Alexander J. Moszczynski ◽  
Hind Amzil ◽  
Michael J. Strong
Keyword(s):  
Neurodegenerative Disease ◽  
Rna Binding ◽  
Cultured Cells ◽  
Rna Binding Proteins ◽  
Metabolic Stress ◽  
Aggregate Formation ◽  
Nucleotide Exchange ◽  
Protein Aggregate ◽  
Inclusion Formation ◽  
Als Patients

AbstractAmyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disease with no known etiology. The formation of pathological protein inclusions, including RNA-binding proteins such as TDP-43 and rho guanine nucleotide exchange factor (RGNEF) are a hallmark of ALS. Despite intensive research, the mechanisms behind protein aggregate formation in ALS remains unclear. We have investigated the role of metabolic stress in protein aggregate formation analyzing how it is relevant to the co-aggregation observed between RGNEF and TDP-43 in motor neurons of ALS patients. Metabolic stress was able to induce formation of micronuclei, small nuclear fragments, in cultured cells. Notably, we observed the formation TDP-43 protein inclusions within micronuclei that co-aggregate with RGNEF and can be released to the cytoplasm. We observed that the leucine-rich domain of RGNEF is critical for its interaction with TDP-43 and localization in micronuclei. Finally, we described that micronuclei-like structures can be found in brain and spinal cord of ALS patients. This work is the first description of protein inclusion formation within micronuclei which also is linked with a neurodegenerative disease. The formation of TDP-43 inclusions within micronuclei induced by metabolic stress is a novel mechanism of protein aggregate formation which may have broad relevance for ALS and other neurodegenerative diseases.

scholarly journals Environmental and genetic factors support the dissociation between α-synuclein aggregation and toxicity

2016 ◽  
Vol 113 (42) ◽  
pp. E6506-E6515 ◽  
Author(s):  
Anna Villar-Piqué ◽  
Tomás Lopes da Fonseca ◽  
Ricardo Sant’Anna ◽  
Éva Mónika Szegö ◽  
Luis Fonseca-Ornelas ◽  
...  
Keyword(s):  
Genetic Factors ◽  
Strong Support ◽  
Structural Features ◽  
Biological Properties ◽  
Neuronal Cultures ◽  
Unique Combination ◽  
Primary Neuronal Cultures ◽  
Intrinsic Factors ◽  
Inclusion Formation ◽  
Neuronal Protein

Synucleinopathies are a group of progressive disorders characterized by the abnormal aggregation and accumulation of α-synuclein (aSyn), an abundant neuronal protein that can adopt different conformations and biological properties. Recently, aSyn pathology was shown to spread between neurons in a prion-like manner. Proteins like aSyn that exhibit self-propagating capacity appear to be able to adopt different stable conformational states, known as protein strains, which can be modulated both by environmental and by protein-intrinsic factors. Here, we analyzed these factors and found that the unique combination of the neurodegeneration-related metal copper and the pathological H50Q aSyn mutation induces a significant alteration in the aggregation properties of aSyn. We compared the aggregation of WT and H50Q aSyn with and without copper, and assessed the effects of the resultant protein species when applied to primary neuronal cultures. The presence of copper induces the formation of structurally different and less-damaging aSyn aggregates. Interestingly, these aggregates exhibit a stronger capacity to induce aSyn inclusion formation in recipient cells, which demonstrates that the structural features of aSyn species determine their effect in neuronal cells and supports a lack of correlation between toxicity and inclusion formation. In total, our study provides strong support in favor of the hypothesis that protein aggregation is not a primary cause of cytotoxicity.

scholarly journals Hsp90 and its co-chaperone Sti1 control TDP-43 misfolding and toxicity

2020 ◽  
Author(s):  
Lilian Tsai-Wei Lin ◽  
Abdul Razzaq ◽  
Sonja E. Di Gregorio ◽  
Soojie Hong ◽  
Brendan Charles ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Molecular Chaperones ◽  
Protein Misfolding ◽  
Central Feature ◽  
Dependent Manner ◽  
Cellular Toxicity ◽  
Inclusion Formation ◽  
Dose Dependent ◽  
Lateral Sclerosis ◽  
Strong Capacity

AbstractProtein misfolding is a central feature of most neurodegenerative diseases. Molecular chaperones can modulate the toxicity associated with protein misfolding, but it remains elusive which molecular chaperones and co-chaperones interact with specific misfolded proteins. TDP-43 misfolding and inclusion formation is a hallmark of amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. Using yeast and mammalian neuronal cells we find that Hsp90 and its co-chaperones have a strong capacity to alter TDP-43 misfolding, inclusion formation, aggregation, and cellular toxicity. Our data also demonstrate that impaired Hsp90 function sensitizes cells to TDP-43 toxicity. We further show that the co-chaperone Sti1 specifically interacts with and modulates TDP-43 toxicity in a dose-dependent manner. Our study thus uncovers a previously unrecognized tie between Hsp90, Sti1, TDP-43 misfolding, and its cellular toxicity.

scholarly journals Protein Aggregation is Associated with Acinetobacter baumannii Desiccation Tolerance

2020 ◽  
Vol 8 (3) ◽  
pp. 343 ◽  
Author(s):  
Xun Wang ◽  
Cody G. Cole ◽  
Cory D. DuPai ◽  
Bryan W. Davies
Keyword(s):  
Acinetobacter Baumannii ◽  
Desiccation Tolerance ◽  
Bacterial Pathogen ◽  
Protein Aggregates ◽  
Cellular Protein ◽  
Aggregate Formation ◽  
Growth Phases ◽  
Protein Aggregate ◽  
Factors Influencing ◽  
Cellular Aggregates

Desiccation tolerance has been implicated as an important characteristic that potentiates the spread of the bacterial pathogen Acinetobacter baumannii on dry surfaces. Here we explore several factors influencing desiccation survival of A. baumannii. At the macroscale level, we find that desiccation tolerance is influenced by cell density and growth phase. A transcriptome analysis indicates that desiccation represents a unique state for A. baumannii compared to commonly studied growth phases and strongly influences pathways responsible for proteostasis. Remarkably, we find that an increase in total cellular protein aggregates, which is often considered deleterious, correlates positively with the ability of A. baumannii to survive desiccation. We show that inducing protein aggregate formation prior to desiccation increases survival and, importantly, that proteins incorporated into cellular aggregates can retain activity. Our results suggest that protein aggregates may promote desiccation tolerance in A. baumannii through preserving and protecting proteins from damage during desiccation until rehydration occurs.

Whey protein aggregate formation during heating in the presence of κ-carrageenan

2009 ◽  
Vol 115 (4) ◽  
pp. 1479-1485 ◽  
Author(s):  
Kelly L. Flett ◽  
Milena Corredig
Keyword(s):  
Whey Protein ◽  
Aggregate Formation ◽  
Protein Aggregate

scholarly journals p38/MAPK is required for protein aggregate formation and removal by autophagy upon proteasome dysfunction

2022 ◽  
Vol 100 (S267) ◽  
Author(s):  
Ali Koskela ◽  
Johanna Ruuth ◽  
Szabolcs Felszeghy ◽  
Kai Kaarniranta
Keyword(s):  
P38 Mapk ◽  
Aggregate Formation ◽  
Protein Aggregate

scholarly journals DRES-14. PROTEIN AGGREGATE FORMATION PREDICTS CLINICAL RESPONSES TO EGFR TKIs

2018 ◽  
Vol 20 (suppl_6) ◽  
pp. vi78-vi78
Author(s):  
Pim French ◽  
Ya Gao ◽  
Maurice de Wit ◽  
Darlene Mercieca ◽  
Iris de Heer ◽  
...  
Keyword(s):  
Aggregate Formation ◽  
Protein Aggregate ◽  
Clinical Responses ◽  
Egfr Tkis
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