Faculty Opinions recommendation of Widespread protein aggregation as an inherent part of aging in C. elegans.

AbstractAging and fertility are two interconnected processes. From invertebrates to mammals, absence of the germline increases longevity. Here we show that loss of function of sul-2, the Caenorhabditis elegans steroid sulfatase (STS), raises the pool of sulfated steroid hormones, increases longevity and ameliorates protein aggregation diseases. This increased longevity requires factors involved in germline-mediated longevity (daf-16, daf-12, kri-1, tcer-1 and daf-36 genes) although sul-2 mutations do not affect fertility. Interestingly, sul-2 is only expressed in sensory neurons, suggesting a regulation of sulfated hormones state by environmental cues. Treatment with the specific STS inhibitor STX64, as well as with testosterone-derived sulfated hormones reproduces the longevity phenotype of sul-2 mutants. Remarkably, those treatments ameliorate protein aggregation diseases in C. elegans, and STX64 also Alzheimer’s disease in a mammalian model. These results open the possibility of reallocating steroid sulfatase inhibitors or derivates for the treatment of aging and aging related diseases.

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INCREASE IN HSP25 EXTENDS LIFESPAN AND IMPROVES RESPONSE TO TAU TOXICITY THROUGH A CELL, NON-AUTONOMOUS MECHANISM

Innovation in Aging ◽

10.1093/geroni/igz038.2678 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

pp. S730-S730

Author(s):

Karl Rodriguez

Keyword(s):

Stress Response ◽

Protein Aggregation ◽

Cell Types ◽

Over Expression ◽

C Elegans ◽

Expression Of Genes ◽

Stress Response Pathway ◽

A Cell ◽

Cytotoxic Proteins ◽

Improve Health

Abstract The accrual of aggregation-prone cytotoxic proteins underlies neural pathologies seen in aging, Alzheimer’s disease and other dementias. Recent evidence indicates that heat shock protein 25kDa (HSP25) interacts with tau. To demonstrate a causal role for HSP25 in these pathologies, we overexpressed HSP25 protein in worms. This manipulation led to an increase in life span. Moreover, the longevity-effect was associated with increased expression of genes downstream of the SKN-1/Nrf2 stress-response transcription factor. HSP25 over-expression also reduces aggregate pathology and extends lifespan in a C. elegans neuronal-specific, aggregate-prone tau model . We propose that over-expression of HSP25 could provide protection from protein aggregation induced neurodegeneration. However, it is not yet clear whether this HSP25 effect could be efficaciously provided exogenously by other cell types. Thus, we will test whether increased peripheral HSP25 will reduce protein aggregation and stimulate a global Skn-1 stress-response pathway, reduce toxicity in neurons, and improve health outcomes.

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Genome-wide RNAi screen and in vivo protein aggregation reporters identify degradation of damaged proteins as an essential hypertonic stress response

AJP Cell Physiology ◽

10.1152/ajpcell.00450.2008 ◽

2008 ◽

Vol 295 (6) ◽

pp. C1488-C1498 ◽

Cited By ~ 51

Author(s):

Keith P. Choe ◽

Kevin Strange

Keyword(s):

Protein Aggregation ◽

Ubiquitin Proteasome System ◽

Protein Damage ◽

Cell Shrinkage ◽

Protein Aggregate ◽

Fluorescent Reporter ◽

Hypertonic Stress ◽

C Elegans ◽

Endogenous Proteins

The damaging effects of hypertonic stress on cellular proteins are poorly defined, and almost nothing is known about the pathways that detect and repair hypertonicity-induced protein damage. To begin addressing these problems, we screened ∼19,000 Caenorhabditis elegans genes by RNA interference (RNAi) feeding and identified 40 that are essential for survival during acute hypertonic stress. Half (20 of 40) of these genes encode proteins that function to detect, transport, and degrade damaged proteins, including components of the ubiquitin-proteasome system, endosomal sorting complexes, and lysosomes. High-molecular-weight ubiquitin conjugates increase during hypertonic stress, suggesting a global change in the ubiquitinylation state of endogenous proteins. Using a polyglutamine-containing fluorescent reporter, we demonstrate that cell shrinkage induces rapid protein aggregation in vivo and that many of the genes that are essential for survival during hypertonic stress function to prevent accumulation of aggregated proteins. High levels of urea, a strong protein denaturant, do not cause aggregation, suggesting that factors such as macromolecular crowding also contribute to protein aggregate formation during cell shrinkage. Acclimation of C. elegans to mild hypertonicity dramatically increases the osmotic threshold for protein aggregation, demonstrating that protein aggregation-inhibiting pathways are activated by osmotic stress. Our studies demonstrate that hypertonic stress induces protein damage in vivo and that detection and degradation of damaged proteins are essential mechanisms for survival under hypertonic conditions.

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Optimal strategies for inhibition of protein aggregation

10.1101/456590 ◽

2018 ◽

Author(s):

Thomas C. T. Michaels ◽

Christoph A. Weber ◽

L. Mahadevan

Keyword(s):

Protein Aggregation ◽

Model Organism ◽

Optimal Strategies ◽

Secondary Nucleation ◽

Treatment Protocols ◽

C Elegans ◽

Molecular Events ◽

And Control ◽

Opening Up ◽

Viable Treatment

AbstractProtein aggregation has been implicated in many diseases.1-7 Therapeutic strategies for these diseases propose the use of drugs to inhibit specific molecular events during the aggregation process.8-11 However, viable treatment protocols require balancing the efficacy of the drug with its toxicity while accounting for the underlying events of aggregation and inhibition at the molecular level. Here, we combine aggregation kinetics and control theory to determine optimal protocols which prevent protein aggregation via specific reaction pathways. We find that the optimal inhibition of primary and fibril-dependent secondary nucleation require fundamentally different drug administration protocols. We test the efficacy of our approach on experimental data for Amyloid-β aggregation of Alzheimer’s disease in the model organism C. elegans. Our results pose and answer the question of the link between the molecular basis of protein aggregation and optimal strategies for inhibiting it, opening up new avenues for the design of rational therapies to control pathological protein aggregation.

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Systemic regulation of mitochondria by germline proteostasis prevents protein aggregation in the soma of C. elegans

Science Advances ◽

10.1126/sciadv.abg3012 ◽

2021 ◽

Vol 7 (26) ◽

pp. eabg3012

Author(s):

Giuseppe Calculli ◽

Hyun Ju Lee ◽

Koning Shen ◽

Uyen Pham ◽

Marija Herholz ◽

...

Keyword(s):

Stem Cells ◽

Protein Aggregation ◽

Germ Line ◽

Wnt Signaling Pathway ◽

Germline Stem Cells ◽

C Elegans ◽

Unfolded Protein ◽

Somatic Tissues ◽

Intracellular Changes ◽

The Unfolded Protein Response

Protein aggregation causes intracellular changes in neurons, which elicit signals to modulate proteostasis in the periphery. Beyond the nervous system, a fundamental question is whether other organs also communicate their proteostasis status to distal tissues. Here, we examine whether proteostasis of the germ line influences somatic tissues. To this end, we induce aggregation of germline-specific PGL-1 protein in germline stem cells of Caenorhabditis elegans. Besides altering the intracellular mitochondrial network of germline cells, PGL-1 aggregation also reduces the mitochondrial content of somatic tissues through long-range Wnt signaling pathway. This process induces the unfolded protein response of the mitochondria in the soma, promoting somatic mitochondrial fragmentation and aggregation of proteins linked with neurodegenerative diseases such as Huntington’s and amyotrophic lateral sclerosis. Thus, the proteostasis status of germline stem cells coordinates mitochondrial networks and protein aggregation through the organism.

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Therapeutic genetic variation revealed in diverse Hsp104 homologs

eLife ◽

10.7554/elife.57457 ◽

2020 ◽

Vol 9 ◽

Author(s):

Zachary M March ◽

Katelyn Sweeney ◽

Hanna Kim ◽

Xiaohui Yan ◽

Laura M Castellano ◽

...

Keyword(s):

Genetic Variation ◽

Protein Aggregation ◽

Neurodegenerative Disease ◽

Human Cells ◽

C Elegans ◽

Dopaminergic Neurodegeneration ◽

Aaa Protein ◽

Selective Activity

The AAA+ protein disaggregase, Hsp104, increases fitness under stress by reversing stress-induced protein aggregation. Natural Hsp104 variants might exist with enhanced, selective activity against neurodegenerative disease substrates. However, natural Hsp104 variation remains largely unexplored. Here, we screened a cross-kingdom collection of Hsp104 homologs in yeast proteotoxicity models. Prokaryotic ClpG reduced TDP-43, FUS, and α-synuclein toxicity, whereas prokaryotic ClpB and hyperactive variants were ineffective. We uncovered therapeutic genetic variation among eukaryotic Hsp104 homologs that specifically antagonized TDP-43 condensation and toxicity in yeast and TDP-43 aggregation in human cells. We also uncovered distinct eukaryotic Hsp104 homologs that selectively antagonized α-synuclein condensation and toxicity in yeast and dopaminergic neurodegeneration in C. elegans. Surprisingly, this therapeutic variation did not manifest as enhanced disaggregase activity, but rather as increased passive inhibition of aggregation of specific substrates. By exploring natural tuning of this passive Hsp104 activity, we elucidated enhanced, substrate-specific agents that counter proteotoxicity underlying neurodegeneration.

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Protein aggregation contributes to aging in C. elegans

Lab Animal ◽

10.1038/s41684-019-0335-5 ◽

2019 ◽

Vol 48 (7) ◽

pp. 200-200

Author(s):

Alexandra Le Bras

Keyword(s):

Protein Aggregation ◽

C Elegans

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