scholarly journals PIP3-binding proteins promote age-dependent protein aggregation and limit survival in C. elegans

Oncotarget ◽  
2016 ◽  
Vol 7 (31) ◽  
pp. 48870-48886 ◽  
Author(s):  
Srinivas Ayyadevara ◽  
Meenakshisundaram Balasubramaniam ◽  
Jay Johnson ◽  
Ramani Alla ◽  
Samuel G. Mackintosh ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Binding Proteins ◽  
C Elegans ◽  
Age Dependent ◽  
Dependent Protein

scholarly journals Intrinsically aggregation-prone proteins form amyloid-like aggregates and contribute to tissue aging in Caenorhabditis elegans

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Chaolie Huang ◽  
Sara Wagner-Valladolid ◽  
Amberley D Stephens ◽  
Raimund Jung ◽  
Chetan Poudel ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Aging Process ◽  
Amyloid Fibrils ◽  
Functional Decline ◽  
Molecular Feature ◽  
C Elegans ◽  
Age Dependent ◽  
Dependent Protein ◽  
Tissue Aging ◽  
Different Tissues

Reduced protein homeostasis leading to increased protein instability is a common molecular feature of aging, but it remains unclear whether this is a cause or consequence of the aging process. In neurodegenerative diseases and other amyloidoses, specific proteins self-assemble into amyloid fibrils and accumulate as pathological aggregates in different tissues. More recently, widespread protein aggregation has been described during normal aging. Until now, an extensive characterization of the nature of age-dependent protein aggregation has been lacking. Here, we show that age-dependent aggregates are rapidly formed by newly synthesized proteins and have an amyloid-like structure resembling that of protein aggregates observed in disease. We then demonstrate that age-dependent protein aggregation accelerates the functional decline of different tissues in C. elegans. Together, these findings imply that amyloid-like aggregates contribute to the aging process and therefore could be important targets for strategies designed to maintain physiological functions in the late stages of life.

scholarly journals Intrinsically aggregation-prone proteins form amyloid-like aggregates and contribute to tissue aging in C. elegans

2018 ◽  
Author(s):  
C. Huang ◽  
S. Wagner-Valladolid ◽  
A.D. Stephens ◽  
R. Jung ◽  
C. Poudel ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Amyloid Fibrils ◽  
Functional Decline ◽  
C Elegans ◽  
Amyloid Aggregates ◽  
Age Dependent ◽  
Dependent Protein ◽  
Specific Proteins ◽  
Protein Instability ◽  
Tissue Aging

AbstractReduced protein homeostasis and increased protein instability is a common feature of aging. Yet it remains unclear whether protein instability is a cause of aging. In neurodegenerative diseases and amyloidoses, specific proteins self-assemble into amyloid fibrils and accumulate as pathological solid aggregates in a variety of tissues. More recently, widespread protein aggregation has been described during normal aging, in the absence of disease processes. Until now, an extensive characterization of the nature of age-dependent protein aggregation and its consequences for aging has been lacking. Here, we show that age-dependent aggregates are rapidly formed by newly synthesized proteins and contain amyloid-like structures similar to disease-associated protein aggregates. Moreover, we demonstrate that age-dependent protein aggregation accelerates the functional decline of different tissues in C. elegans. Together, these finding reveal that the formation of amyloid aggregates is a generic problem of aging and likely to be an important target for strategies designed to maintain physiological functions in later stages of life.

scholarly journals Drosophila p38 MAPK Interacts with BAG-3/starvin to Regulate Age-dependent Protein Homeostasis

2019 ◽  
Author(s):  
Sarah M. Ryan ◽  
Michael Almassey ◽  
Amelia M. Burch ◽  
Gia Ngo ◽  
Julia M. Martin ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
P38 Mapk ◽  
Protein Aggregates ◽  
Protein Homeostasis ◽  
Selective Autophagy ◽  
Age Related ◽  
Age Dependent ◽  
Dependent Protein ◽  
Locomotor Behaviors ◽  
The Relationship

SummaryAs organisms age, they often accumulate protein aggregates that are thought to be toxic, potentially leading to age-related diseases. This accumulation of protein aggregates is partially attributed to a failure to maintain protein homeostasis. A variety of genetic factors have been linked to longevity, but how these factors also contribute to protein homeostasis is not completely understood. In order to understand the relationship between aging and protein aggregation, we tested how a gene that regulates lifespan and age-dependent locomotor behaviors, p38 MAPK (p38Kb), influences protein homeostasis as an organism ages. We find that p38Kb regulates age-dependent protein aggregation through an interaction with the Chaperone-Assisted Selective Autophagy complex. Furthermore, we have identified Lamin as an age-dependent target of p38Kb and the Chaperone-Assisted Selective Autophagy complex.

scholarly journals A genetic screen identifies processes that couple oocyte maturation to proteostasis in the immortal C. elegans germ lineage

2020 ◽  
Author(s):  
Madhuja Samaddar ◽  
Jérôme Goudeau ◽  
Melissa Sanchez ◽  
David H. Hall ◽  
K. Adam Bohnert ◽  
...  
Keyword(s):  
Oocyte Maturation ◽  
Cell Biology ◽  
Cell Lineage ◽  
Genetic Screen ◽  
Protein Aggregate ◽  
C Elegans ◽  
Age Dependent ◽  
Dependent Protein ◽  
Atp Generation ◽  
And Function

AbstractSomatic cells age and die, but the germ-cell lineage is immortal. In C. elegans, oocyte-maturation signals from sperm trigger the clearance of carbonylated proteins and protein aggregates. Here, we explore the cell biology of this proteostasis renewal in the context of a whole-genome RNAi screen for knockdowns that interfere with aggregate clearance. Oocyte-maturation signals are known to trigger protein-aggregate removal via lysosome acidification, and our findings suggest that lysosomes are acidified as a consequence of changes in ER morphology and function that permit assembly of the lysosomal V-ATPase. Once lysosomes are acidified, our genetic findings support the model that they remove aggregates by microautophagy. We also define two functions for mitochondria in this proteostasis renewal, both of which appear to be independent of mitochondrial ATP generation. Finally, many genes from the screen also regulate lysosome acidification and age-dependent protein aggregation in the soma, suggesting a fundamental mechanistic link between proteostasis renewal in the germline and the maintenance of the soma.

scholarly journals Age-Dependent Protein Aggregation Initiates Amyloid-β Aggregation

2017 ◽  
Vol 9 ◽  
Author(s):  
Nicole Groh ◽  
Anika Bühler ◽  
Chaolie Huang ◽  
Ka Wan Li ◽  
Pim van Nierop ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Amyloid Β ◽  
Age Dependent ◽  
Dependent Protein

scholarly journals Chaperone AMPylation modulates aggregation and toxicity of neurodegenerative disease-associated polypeptides

2017 ◽  
Author(s):  
Matthias C. Truttmann ◽  
David Pincus ◽  
Hidde L. Ploegh
Keyword(s):  
Protein Aggregation ◽  
Neurodegenerative Disease ◽  
Protein Modification ◽  
Amyloid Β ◽  
Protein Aggregates ◽  
Unfolded Proteins ◽  
C Elegans ◽  
Dependent Protein ◽  
Cellular Tolerance

AbstractProteostasis is critical to maintain organismal viability, a process counteracted by aging-dependent protein aggregation. Chaperones of the heat shock protein (HSP) family help control proteostasis by reducing the burden of unfolded proteins. They also oversee the formation of protein aggregates. Here, we explore how AMPylation – a post-translational protein modification that has emerged as a powerful modulator of HSP70 activity – influences the dynamics of protein aggregation. We find that adjustments of cellular AMPylation levels in C.elegans directly affect aggregation properties and associated toxicity of amyloid-β (Aβ), of a polyglutamine (polyQ)- extended polypeptide and of α-synuclein (α-syn). Expression of a constitutively active C. elegans AMPylase Fic-1(E274G) under its own promoter expedites aggregation of Aβ and α-syn, and drastically reduces their toxicity. A deficiency in AMPylation decreases the cellular tolerance for aggregation-prone polyQ proteins and alters their aggregation behavior. Over-expression of Fic-1(E274G) interferes with cell survival and larval development, underscoring the need for tight control of AMPylase activity in vivo. We thus define a link between HSP70 AMPylation and the dynamics of protein aggregation in neurodegenerative disease models. Our results are consistent with a cyto-protective, rather than a cytotoxic role for such protein aggregates.

scholarly journals Chaperone AMPylation modulates aggregation and toxicity of neurodegenerative disease-associated polypeptides

2018 ◽  
Vol 115 (22) ◽  
pp. E5008-E5017 ◽  
Author(s):  
Matthias C. Truttmann ◽  
David Pincus ◽  
Hidde L. Ploegh
Keyword(s):  
Protein Aggregation ◽  
Neurodegenerative Disease ◽  
Protein Modification ◽  
Amyloid Β ◽  
Protein Aggregates ◽  
C Elegans ◽  
Dependent Protein ◽  
Cellular Tolerance ◽  
Posttranslational Protein Modification

Proteostasis is critical to maintain organismal viability, a process counteracted by aging-dependent protein aggregation. Chaperones of the heat shock protein (HSP) family help control proteostasis by reducing the burden of unfolded proteins. They also oversee the formation of protein aggregates. Here, we explore how AMPylation, a posttranslational protein modification that has emerged as a powerful modulator of HSP70 activity, influences the dynamics of protein aggregation. We find that adjustments of cellular AMPylation levels in Caenorhabditis elegans directly affect aggregation properties and associated toxicity of amyloid-β (Aβ), of a polyglutamine (polyQ)-extended polypeptide, and of α-synuclein (α-syn). Expression of a constitutively active C. elegans AMPylase FIC-1(E274G) under its own promoter expedites aggregation of Aβ and α-syn, and drastically reduces their toxicity. A deficiency in AMPylation decreases the cellular tolerance for aggregation-prone polyQ proteins and alters their aggregation behavior. Overexpression of FIC-1(E274G) interferes with cell survival and larval development, underscoring the need for tight control of AMPylase activity in vivo. We thus define a link between HSP70 AMPylation and the dynamics of protein aggregation in neurodegenerative disease models. Our results are consistent with a cytoprotective, rather than a cytotoxic, role for such protein aggregates.

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