scholarly journals Therapeutic genetic variation revealed in diverse Hsp104 homologs

eLife ◽  
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.

scholarly journals Therapeutic genetic variation revealed in diverse Hsp104 homologs

2020 ◽  
Author(s):  
Zachary M. March ◽  
Katelyn Sweeney ◽  
Hanna Kim ◽  
Xiaohui Yan ◽  
Laura M. Castellano ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Neurodegenerative Diseases ◽  
Protein Aggregation ◽  
Neurodegenerative Disease ◽  
Chaperone Activity ◽  
C Elegans ◽  
Condensate Formation ◽  
Natural Variants ◽  
Aaa Protein ◽  
Selective Activity

ABSTRACTThe AAA+ protein disaggregase, Hsp104, increases fitness under stress by reversing stress-induced protein aggregation. We have engineered potentiated Hsp104 variants to antagonize proteotoxic misfolding linked to human neurodegenerative diseases. However, these Hsp104 variants can exhibit off-target toxicity, which may limit their therapeutic utility. Hsp104 is conserved among all nonmetazoan eukaryotes, which raises the possibility that natural variants might exist with enhanced, selective activity against neurodegenerative disease substrates. To assess this possibility, we screened a cross-kingdom collection of Hsp104 homologs in several yeast proteotoxicity models. We uncovered therapeutic genetic variation among several Hsp104 homologs that specifically antagonize TDP-43 or α-synuclein condensate formation and toxicity in yeast, human cells, and C. elegans. Surprisingly, this variation manifested as increased passive chaperone activity, distinct from disaggregase activity, which neutralizes proteotoxicity of specific substrates. Thus, by exploring natural tuning of passive chaperone activity we elucidated enhanced, substrate-specific agents to counter proteotoxicity underlying neurodegenerative disease.

scholarly journals Tuning Hsp104 specificity to selectively detoxify α-synuclein

2020 ◽  
Author(s):  
Korrie L. Mack ◽  
Hanna Kim ◽  
Meredith E. Jackrel ◽  
JiaBei Lin ◽  
Jamie E. DeNizio ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substrate Specificity ◽  
Neurodegenerative Disease ◽  
Neurodegenerative Disorders ◽  
C Elegans ◽  
Dopaminergic Neurodegeneration ◽  
Aaa Protein ◽  
Target Effects

SummaryHsp104 is an AAA+ protein disaggregase that solubilizes and reactivates proteins trapped in aggregated states. We have engineered potentiated Hsp104 variants to mitigate toxic misfolding of α-synuclein, TDP-43, and FUS implicated in fatal neurodegenerative disorders. Though potent disaggregases, these enhanced Hsp104 variants lack substrate specificity, and can have unfavorable off-target effects. Here, to lessen off-target effects, we engineer substrate-specific Hsp104 variants. By altering Hsp104 pore loops that engage substrate, we disambiguate Hsp104 variants that selectively suppress α-synuclein toxicity but not TDP-43 or FUS toxicity. Remarkably, α-synuclein-specific Hsp104 variants emerge that mitigate α-synuclein toxicity via distinct ATPase-dependent mechanisms, involving α-synuclein disaggregation or detoxification of α-synuclein conformers without disaggregation. Importantly, both types of α-synuclein-specific Hsp104 variant reduce dopaminergic neurodegeneration in a C. elegans model of Parkinson’s disease more effectively than non-specific variants. We suggest that increasing the substrate specificity of enhanced disaggregases could be applied broadly to tailor therapeutics for neurodegenerative disease.

scholarly journals Automated longitudinal monitoring of in vivo protein aggregation in neurodegenerative disease C. elegans models

2016 ◽  
Vol 11 (1) ◽  
Author(s):  
Matteo Cornaglia ◽  
Gopalan Krishnamani ◽  
Laurent Mouchiroud ◽  
Vincenzo Sorrentino ◽  
Thomas Lehnert ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Neurodegenerative Disease ◽  
C Elegans

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.

Population Genetics ofCaenorhabditis elegans: The Paradox of Low Polymorphism in a Widespread Species

Genetics ◽  
2003 ◽  
Vol 163 (1) ◽  
pp. 147-157 ◽  
Author(s):  
Arjun Sivasundar ◽  
Jody Hey
Keyword(s):  
Genetic Variation ◽  
Microsatellite Loci ◽  
Population Expansion ◽  
Widespread Species ◽  
C Elegans ◽  
Model Research ◽  
The World ◽  
Natural Isolates ◽  
History Of ◽  
Low Levels

AbstractCaenorhabditis elegans has become one of the most widely used model research organisms, yet we have little information on evolutionary processes and recent evolutionary history of this widespread species. We examined patterns of variation at 20 microsatellite loci in a sample of 23 natural isolates of C. elegans from various parts of the world. One-half of the loci were monomorphic among all strains, and overall genetic variation at microsatellite loci was low, relative to most other species. Some population structure was detected, but there was no association between the genetic and geographic distances among different natural isolates. Thus, despite the nearly worldwide occurrence of C. elegans, little evidence was found for local adaptation in strains derived from different parts of the world. The low levels of genetic variation within and among populations suggest that recent colonization and population expansion might have occurred. However, the patterns of variation are not consistent with population expansion. A possible explanation for the observed patterns is the action of background selection to reduce polymorphism, coupled with ongoing gene flow among populations worldwide.

scholarly journals Steroid hormones sulfatase inactivation extends lifespan and ameliorates age-related diseases

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Mercedes M. Pérez-Jiménez ◽  
José M. Monje-Moreno ◽  
Ana María Brokate-Llanos ◽  
Mónica Venegas-Calerón ◽  
Alicia Sánchez-García ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Caenorhabditis Elegans ◽  
Protein Aggregation ◽  
Steroid Hormones ◽  
Sensory Neurons ◽  
Environmental Cues ◽  
Steroid Sulfatase ◽  
Loss Of Function ◽  
C Elegans ◽  
Age Related

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.

scholarly journals Mitophagy Modulation, a New Player in the Race against ALS

2021 ◽  
Vol 22 (2) ◽  
pp. 740
Author(s):  
Enrique Madruga ◽  
Inés Maestro ◽  
Ana Martínez
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Protein Aggregation ◽  
Neurodegenerative Disease ◽  
Effective Treatment ◽  
Unknown Etiology ◽  
Drug Candidates ◽  
Relevant Evidence ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease that usually results in respiratory paralysis in an interval of 2 to 4 years. ALS shows a multifactorial pathogenesis with an unknown etiology, and currently lacks an effective treatment. The vast majority of patients exhibit protein aggregation and a dysfunctional mitochondrial accumulation in their motoneurons. As a result, autophagy and mitophagy modulators may be interesting drug candidates that mitigate key pathological hallmarks of the disease. This work reviews the most relevant evidence that correlate mitophagy defects and ALS, and discusses the possibility of considering mitophagy as an interesting target in the search for an effective treatment for ALS.

The Cryo-EM Effect: Structural Biology of Neurodegenerative Disease Proteostasis Factors

2021 ◽  
Author(s):  
Benjamin C Creekmore ◽  
Yi-Wei Chang ◽  
Edward B Lee
Keyword(s):  
Neurodegenerative Diseases ◽  
Protein Aggregation ◽  
Neurodegenerative Disease ◽  
Electron Tomography ◽  
Ubiquitin Proteasome System ◽  
26S Proteasome ◽  
X Ray Crystallography ◽  
New Information ◽  
A Cell ◽  
Regulate Protein

Abstract Neurodegenerative diseases are characterized by the accumulation of misfolded proteins. This protein aggregation suggests that abnormal proteostasis contributes to aging-related neurodegeneration. A better fundamental understanding of proteins that regulate proteostasis may provide insight into the pathophysiology of neurodegenerative disease and may perhaps reveal novel therapeutic opportunities. The 26S proteasome is the key effector of the ubiquitin-proteasome system responsible for degrading polyubiquitinated proteins. However, additional factors, such as valosin-containing protein (VCP/p97/Cdc48) and C9orf72, play a role in regulation and trafficking of substrates through the normal proteostasis systems of a cell. Nonhuman AAA+ ATPases, such as the disaggregase Hsp104, also provide insights into the biochemical processes that regulate protein aggregation. X-ray crystallography and cryo-electron microscopy (cryo-EM) structures not bound to substrate have provided meaningful information about the 26S proteasome, VCP, and Hsp104. However, recent cryo-EM structures bound to substrate have provided new information about the function and mechanism of these proteostasis factors. Cryo-EM and cryo-electron tomography data combined with biochemical data have also increased the understanding of C9orf72 and its role in maintaining proteostasis. These structural insights provide a foundation for understanding proteostasis mechanisms with near-atomic resolution upon which insights can be gleaned regarding the pathophysiology of neurodegenerative diseases.

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