Axon Injury-Induced Autophagy Activation Is Impaired in a C. elegans Model of Tauopathy

Autophagy is a conserved pathway that plays a key role in cell homeostasis in normal settings, as well as abnormal and stress conditions. Autophagy dysfunction is found in various neurodegenerative diseases, although it remains unclear whether autophagy impairment is a contributor or consequence of neurodegeneration. Axonal injury is an acute neuronal stress that triggers autophagic responses in an age-dependent manner. In this study, we investigate the injury-triggered autophagy response in a C. elegans model of tauopathy. We found that transgenic expression of pro-aggregant Tau, but not the anti-aggregant Tau, abolished axon injury-induced autophagy activation, resulting in a reduced axon regeneration capacity. Furthermore, axonal trafficking of autophagic vesicles were significantly reduced in the animals expressing pro-aggregant F3ΔK280 Tau, indicating that Tau aggregation impairs autophagy regulation. Importantly, the reduced number of total or trafficking autophagic vesicles in the tauopathy model was not restored by the autophagy activator rapamycin. Loss of PTL-1, the sole Tau homologue in C. elegans, also led to impaired injury-induced autophagy activation, but with an increased basal level of autophagic vesicles. Therefore, we have demonstrated that Tau aggregation as well as Tau depletion both lead to disruption of injury-induced autophagy responses, suggesting that aberrant protein aggregation or microtubule dysfunction can modulate autophagy regulation in neurons after injury.

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Deletion of murine tau gene increases tau aggregation in a human mutant tau transgenic mouse model

Biochemical Society Transactions ◽

10.1042/bst0381001 ◽

2010 ◽

Vol 38 (4) ◽

pp. 1001-1005 ◽

Cited By ~ 14

Author(s):

Kunie Ando ◽

Karelle Leroy ◽

Céline Heraud ◽

Anna Kabova ◽

Zehra Yilmaz ◽

...

Keyword(s):

Mouse Model ◽

Transgenic Mouse ◽

Double Mutant ◽

Transgenic Mouse Model ◽

Tau Proteins ◽

Dependent Manner ◽

Age Dependent ◽

Ad Alzheimer’S Disease ◽

Tau Aggregation ◽

The Brain

We have reported previously a tau transgenic mouse model (Tg30tau) overexpressing human 4R1N double-mutant tau (P301S and G272V) and that develops AD (Alzheimer's disease)-like NFTs (neurofibrillary tangles) in an age-dependent manner. Since murine tau might interfere with the toxic effects of human mutant tau, we set out to analyse the phenotype of our Tg30tau model in the absence of endogenous murine tau with the aim to reproduce more faithfully a model of human tauopathy. By crossing the Tg30tau line with TauKO (tau-knockout) mice, we have obtained a new mouse line called Tg30×TauKO that expresses only exogenous human double-mutant 4R1N tau. Whereas Tg30×TauKO mice express fewer tau proteins compared with Tg30tau, they exhibit augmented sarkosyl-insoluble tau in the brain and an increased number of Gallyas-positive NFTs in the hippocampus. Taken together, exclusion of murine tau causes accelerated tau aggregation during aging of this mutant tau transgenic model.

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Corrigendum to: IQ motif containing D (IQCD), a new acrosomal protein involved in the acrosome reaction and fertilisation

Reproduction Fertility and Development ◽

10.1071/rd18416_co ◽

2019 ◽

Vol 31 (5) ◽

pp. 1033

Author(s):

Peng Zhang ◽

Wanjun Jiang ◽

Na Luo ◽

Wenbing Zhu ◽

Liqing Fan

Keyword(s):

Acrosome Reaction ◽

Development Stage ◽

Seminiferous Tubules ◽

Testicular Development ◽

Dependent Manner ◽

Iq Motif ◽

C Elegans ◽

Fertilisation Rate ◽

Age Dependent ◽

Mammalian Spermatozoa

The acrosome is single, large, dense-core secretory granule overlying the nucleus of most mammalian spermatozoa. Its exocytosis, the acrosome reaction, is a crucial event during fertilisation. In this study we identified a new acrosome-associated gene, namely IQ motif containing D (IQCD), expressed nearly in multiple tissues with highest expression levels in the testis. In mouse testis, Iqcd transcript accumulated from Postnatal Day (PND) 1 to adulthood. However, expression of IQCD protein at the testicular development stage started primarily from PND 18 and increased in an age-dependent manner until plateauing in adulthood. IQCD was primarily accumulated in the acrosome area of round and elongating spermatids within seminiferous tubules of the testes during the late stage of spermiogenesis; this immunolocalisation pattern is similar in mice and humans. IQCD levels in spermatozoa were significantly lower in IVF patients with total fertilisation failure or a low fertilisation rate than in healthy men. Anti-IQCD antibody significantly inhibited the acrosome reaction and slightly reduced protein tyrosine phosphorylation levels in human spermatozoa, but specifically blocked murine IVF. IQCD interacted with mammalian homolog of C. elegans uncoordinated gene 13 (Munc13) in spermatozoa and may participate in acrosome exocytosis. In conclusion, this study identified a new acrosomal protein, namely IQCD, which is involved in fertilisation and the acrosome reaction.

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IQ motif containing D (IQCD), a new acrosomal protein involved in the acrosome reaction and fertilisation

Reproduction Fertility and Development ◽

10.1071/rd18416 ◽

2019 ◽

Vol 31 (5) ◽

pp. 898 ◽

Cited By ~ 1

Author(s):

Peng Zhang ◽

Wanjun Jiang ◽

Na Luo ◽

Wenbing Zhu ◽

Liqing Fan

Keyword(s):

Acrosome Reaction ◽

Development Stage ◽

Seminiferous Tubules ◽

Testicular Development ◽

Dependent Manner ◽

Iq Motif ◽

C Elegans ◽

Fertilisation Rate ◽

Age Dependent ◽

Mammalian Spermatozoa

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Modeling of a negative feedback mechanism explains age-dependent genetic architecture in reproduction in domesticated C. elegans strains

10.1101/114348 ◽

2017 ◽

Author(s):

Edward E. Large ◽

Raghavendra Padmanabhan ◽

Kathie L. Watkins ◽

Richard F. Campbell ◽

Wen Xu ◽

...

Keyword(s):

Negative Feedback ◽

Effect Size ◽

Genetic Variants ◽

Communication Systems ◽

Genetic Architecture ◽

Egg Laying ◽

Biological Traits ◽

Dependent Manner ◽

C Elegans ◽

Age Dependent

ABSTRACTMost biological traits and common diseases have a strong but complex genetic basis, controlled by large numbers of genetic variants with small contributions to a trait or disease risk. The effect-size of most genetic variants is not absolute, but can depend on a number of factors including the age and genetic background of an organism. In order to understand the mechanisms that cause these changes, we are studying heritable trait differences between two domesticated strains of C. elegans. We previously identified a major effect locus, caused by a mutation in a component of the NURF chromatin remodeling complex, that regulated reproductive output in an age-dependent manner. The effect-size of this locus changes from positive to negative over the course of an animal’s reproductive lifespan. Using a previously published macroscale model of egg-laying rate in C. elegans, we show how time-dependent effect-size can be explained by an unequal use of sperm combined with negative feedback between sperm and ovulation rate. We validate a number of key predictions of this model using controlled mating experiments and quantification of oogenesis and sperm use. By incorporating this model into QTL mapping, we identify and partition new QTLs into specific aspects of the egg-laying process. Finally, we show how epistasis between two genetic variants is predicted by this modeling as a consequence of unequal use of sperm. This work demonstrates how modeling of multicellular communication systems can improve our ability to predict and understand the role of genetic variation on a complex phenotype. Negative autoregulatory feedback loops, common in transcriptional regulation, could play an important role in modifying genetic architecture in other traits.AUTHOR SUMMARYComplex traits are influenced not only by the individual effects of genetic variants, but also how these variants interact with the environment, age, and each other. While complex genetic architectures seem to be ubiquitous in natural traits, little is known about the mechanisms that cause them. Here we identify an example of age-dependent genetic architecture controlling the rate and timing of reproduction in the hermaphroditic nematode C. elegans. Using computational modeling, we demonstrate how this age-dependent genetic architecture can arise as a consequence of two factors: hormonal feedback on oocytes mediated by major sperm protein (MSP) released by sperm stored in the spermatheca and life history differences in sperm use caused by genetic variants. Our work also suggests how age-dependent epistasis can emerge from multicellular feedback systems.

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The PP2A/4/6 subfamily of phosphoprotein phosphatases regulates DAF-16 during aging and confers resistance to environmental stress in postreproductive adult C. elegans

10.1101/2020.02.18.953687 ◽

2020 ◽

Author(s):

Rebecca S. Rivard ◽

Julia M. Morris ◽

Matthew J. Youngman

Keyword(s):

Environmental Stress ◽

Transcriptional Activity ◽

Reverse Genetics ◽

Dependent Manner ◽

C Elegans ◽

Forkhead Box ◽

Phosphoprotein Phosphatases ◽

Complex Functions ◽

Age Dependent ◽

Foxo Transcription Factors

AbstractInsulin and insulin-like growth factors are longevity determinants that negatively regulate Forkhead box class O (FoxO) transcription factors. In C. elegans mutations that constitutively activate DAF-16, the ortholog of mammalian FoxO3a, extend lifespan by two-fold. While environmental insults induce DAF-16 activity in younger animals, it also becomes activated in an age-dependent manner in the absence of stress, modulating gene expression well into late adulthood. The mechanism by which DAF-16 activity is regulated during aging has not been defined. Since phosphorylation of DAF-16 generally leads to its inhibition, we asked whether phosphatases might be necessary for its increased transcriptional activity in adult C. elegans. We focused on the PP2A/4/6 subfamily of phosphoprotein phosphatases, members of which had been implicated to regulate DAF-16 under low insulin signaling conditions but had not been investigated during aging in wildtype animals. Using reverse genetics, we functionally characterized all C. elegans orthologs of human catalytic, regulatory, and scaffolding subunits of PP2A/4/6 holoenzymes in postreproductive adults. We found that PP2A complex constituents PAA-1 and PPTR-1 regulate DAF-16 during aging and that they cooperate with the catalytic subunit LET-92 to protect adult animals from ultraviolet radiation. PP4 complex members PPH-4.1/4.2, SMK-1, and PPFR-2 also appear to regulate DAF-16 in an age-dependent manner, and they contribute to innate immunity. Interestingly, SUR-6 but no other subunit of the PP2A complex was necessary for the survival of pathogen-infected animals, suggesting that a heterotypic PP4 complex functions during aging. Finally, we found that PP6 complex constituents PPH-6 and SAPS-1 contribute to host defense during aging, apparently without affecting DAF-16 transcriptional activity. Our studies indicate that a set of PP2A/4/6 complexes protect adult C. elegans from environmental stress, thus preserving healthspan. Therefore, along with their functions in cell division and development, the PP2A/4/6 phosphatases also appear to play critical roles later in life.

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Role of oxidation of excitation-contraction coupling machinery in age-dependent loss of muscle function in C. elegans

10.1101/2021.12.05.471286 ◽

2021 ◽

Author(s):

Haikel Dridi ◽

Frances Forrester ◽

Alisa Umanskaya ◽

Wenjun Xie ◽

Steven Reiken ◽

...

Keyword(s):

Exercise Capacity ◽

Muscle Function ◽

Body Wall ◽

Body Wall Muscle ◽

Macromolecular Complex ◽

Mammalian Skeletal Muscle ◽

Dependent Manner ◽

C Elegans ◽

Reduced Body ◽

Age Dependent

ABSTRACTAge-dependent loss of body wall muscle function and impaired locomotion occur within 2 weeks in C. elegans; however, the underlying mechanism has not been fully elucidated. In humans, age-dependent loss of muscle function occurs at about 80 years of age and has been linked to dysfunction of ryanodine receptor (RyR)/intracellular calcium (Ca2+) release channels on the sarcoplasmic reticulum (SR). Mammalian skeletal muscle RyR1 channels undergo age-related remodeling due to oxidative overload, leading to loss of the stabilizing subunit calstabin1 (FKBP12) from the channel macromolecular complex. This destabilizes the closed state of the channel resulting in intracellular Ca2+ leak, reduced muscle function, and impaired exercise capacity. We now show that the C. elegans RyR homolog, UNC-68, exhibits a remarkable degree of evolutionary conservation with mammalian RyR channels and similar age-dependent dysfunction. Like RyR1 in mammals UNC-68 encodes a protein that comprises a macromolecular complex which includes the calstabin1 homolog FKB-2 and is immunoreactive with antibodies raised against the RyR1 complex. Further, as in aged mammals, UNC-68 is oxidized and depleted of FKB-2 in an age-dependent manner, resulting in “leaky” channels, depleted SR Ca2+ stores, reduced body wall muscle Ca2+ transients, and age-dependent muscle weakness. FKB-2 (ok3007)-deficient worms exhibit reduced exercise capacity. Pharmacologically induced oxidization of UNC-68 and depletion of FKB-2 from the channel independently caused reduced body wall muscle Ca2+ transients. Preventing FKB-2 depletion from the UNC-68 macromolecular complex using the Rycal drug S107 improved muscle Ca2+ transients and function. Taken together, these data suggest that UNC-68 oxidation plays a role in age-dependent loss of muscle function. Remarkably, this age-dependent loss of muscle function induced by oxidative overload, which takes ~2 years in mice and ~80 years in humans, occurs in less than 2-3 weeks in C. elegans, suggesting that reduced anti-oxidant capacity may contribute to the differences in life span amongst species.

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The PP2A/4/6 subfamily of phosphoprotein phosphatases regulates DAF-16 and confers resistance to environmental stress in postreproductive adult C. elegans

PLoS ONE ◽

10.1371/journal.pone.0229812 ◽

2020 ◽

Vol 15 (12) ◽

pp. e0229812

Author(s):

Rebecca S. Rivard ◽

Julia M. Morris ◽

Matthew J. Youngman

Keyword(s):

Environmental Stress ◽

Transcriptional Activity ◽

Reverse Genetics ◽

Dependent Manner ◽

C Elegans ◽

Forkhead Box ◽

Phosphoprotein Phosphatases ◽

Age Dependent ◽

Foxo Transcription Factors ◽

Insulin Like Growth Factors

Insulin and insulin-like growth factors are longevity determinants that negatively regulate Forkhead box class O (FoxO) transcription factors. In C. elegans mutations that constitutively activate DAF-16, the ortholog of mammalian FoxO3a, extend lifespan by two-fold. While environmental insults induce DAF-16 activity in younger animals, it also becomes activated in an age-dependent manner in the absence of stress, modulating gene expression well into late adulthood. The mechanism by which DAF-16 activity is regulated during aging has not been defined. Since phosphorylation of DAF-16 generally leads to its inhibition, we asked whether phosphatases might be necessary for its increased transcriptional activity in adult C. elegans. We focused on the PP2A/4/6 subfamily of phosphoprotein phosphatases, members of which had been implicated to regulate DAF-16 under low insulin signaling conditions but had not been investigated during aging in wildtype animals. Using reverse genetics, we functionally characterized all C. elegans orthologs of human catalytic, regulatory, and scaffolding subunits of PP2A/4/6 holoenzymes in postreproductive adults. We found that PP2A complex constituents PAA-1 and PPTR-1 regulate DAF-16 transcriptional activity during aging and that they cooperate with the catalytic subunit LET-92 to protect adult animals from ultraviolet radiation. PP4 complex members PPH-4.1/4.2, and SMK-1 also appear to regulate DAF-16 in an age-dependent manner, and together with PPFR-2 they contribute to innate immunity. Interestingly, SUR-6 but no other subunit of the PP2A complex was necessary for the survival of pathogen-infected animals. Finally, we found that PP6 complex constituents PPH-6 and SAPS-1 contribute to host defense during aging, apparently without affecting DAF-16 transcriptional activity. Our studies indicate that a set of PP2A/4/6 complexes protect adult C. elegans from environmental stress, thus preserving healthspan. Therefore, along with their functions in cell division and development, the PP2A/4/6 phosphatases also appear to play critical roles later in life.

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DAF-16 and SMK-1 contribute to innate immunity during adulthood in Caenorhabditis elegans

10.1101/761312 ◽

2019 ◽

Author(s):

Daniel R. McHugh ◽

Elena Koumis ◽

Michelle Schlaubitz-Garcia ◽

Safae Bennani ◽

Paul Regan ◽

...

Keyword(s):

Innate Immunity ◽

Immune System ◽

Caenorhabditis Elegans ◽

Host Defense ◽

Insulin Signaling ◽

Bacterial Pathogens ◽

Dependent Manner ◽

C Elegans ◽

Age Dependent ◽

Over Time

ABSTRACTAging is accompanied by a progressive decline in immune function termed “immunosenescence”. Deficient surveillance coupled with the impaired function of immune cells compromises host defense in older animals. The dynamic activity of regulatory modules that control immunity appears to underlie age-dependent modifications to the immune system. In the roundworm Caenorhabditis elegans levels of the PMK-1 p38 MAP kinase diminish over time, reducing the expression of immune effectors that clear bacterial pathogens. Along with the PMK-1 pathway, innate immunity in C. elegans is regulated by the insulin signaling pathway. Here we asked whether DAF-16, a Forkhead box (FOXO) transcription factor whose activity is inhibited by insulin signaling, plays a role in host defense later in life. While in younger worms DAF-16 remains in an inactive state unless stimulated by environmental insults, we found that even in the absence of acute stress the transcriptional activity of DAF-16 increases in an age-dependent manner. Beginning in the reproductive phase of adulthood, DAF-16 upregulates a subset of its transcriptional targets, including genes required to kill ingested microbes. Accordingly, DAF-16 has little to no role in larval immunity, but functions specifically during adulthood to confer resistance to bacterial pathogens. We found that DAF-16-mediated immunity in adults requires SMK-1, a regulatory subunit of the PP4 protein phosphatase complex. Our data suggest that as the function of one branch of the innate immune system of C. elegans (PMK-1) declines over time, DAF-16-mediated immunity ramps up to become the predominant means of protecting adults from infection, thus reconfiguring immunity later in life.

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