Tauffenberger A et al. (2012) Aging Cell "Glucose delays age-dependent proteotoxicity."

Velde CV, Tauffenberger A, Alex Parker J, Aulas A, Vaccaro A

[Aging Cell, 2012]

Nutrient availability influences an organism's life history with profound effects on metabolism and lifespan. The association between a healthy lifespan and metabolism is incompletely understood, but a central factor is glucose metabolism. Although glucose is an important cellular energy source, glucose restriction is associated with extended lifespan in simple animals and a reduced incidence of age-dependent pathologies in humans. We report here that glucose enrichment delays mutant polyglutamine, TDP-43, FUS, and amyloid- toxicity in Caenorhabditis elegans models of neurodegeneration by reducing protein misfolding. Dysregulated metabolism is common to neurodegeneration and we show that glucose enrichment is broadly protective against proteotoxicity.

Tauffenberger A et al. (2016) Aging (Albany NY) "Fragile lifespan expansion by dietary mitohormesis in C. elegans."

Parker JA, Tauffenberger A, Vaccaro A

[Aging (Albany NY), 2016]

Mitochondrial function is central to longevity and an imbalance in mitonuclear protein homeostasis activates a protective response called the mitochondrial unfolded protein response (UPRmt). Toxic compounds damaging mitochondria trigger the UPRmt, but at sublethal doses these insults extend lifespan in simple animals like C. elegans. Mitochondria are the main energy suppliers in eukaryotes, but it is not known if diet influences the UPRmt. High dietary glucose reduces lifespan in worms, and we show that high dietary glucose activates the UPRmt to protect against lifespan reduction. While lifelong exposure to glucose reduces lifespan, glucose exposure restricted to developing animals extends lifespan and requires the UPRmt. However, this lifespan extension is abolished by further mitochondrial stress in adult animals. We demonstrate that dietary conditions regulate mitochondrial homeostasis, where induction of the UPRmt during development extends lifespan, but prolonged activation into adulthood reduces lifespan.

Tauffenberger A et al. (2014) PLoS Genet "Heritable transmission of stress resistance by high dietary glucose in Caenorhabditis elegans."

Parker JA, Tauffenberger A

[PLoS Genet, 2014]

Glucose is a major energy source and is a key regulator of metabolism but excessive dietary glucose is linked to several disorders including type 2 diabetes, obesity and cardiac dysfunction. Dietary intake greatly influences organismal survival but whether the effects of nutritional status are transmitted to the offspring is an unresolved question. Here we show that exposing Caenorhabditis elegans to high glucose concentrations in the parental generation leads to opposing negative effects on fecundity, while having protective effects against cellular stress in the descendent progeny. The transgenerational inheritance of glucose-mediated phenotypes is dependent on the insulin/IGF-like signalling pathway and components of the histone H3 lysine 4 trimethylase complex are essential for transmission of inherited phenotypes. Thus dietary over-consumption phenotypes are heritable with profound effects on the health and survival of descendants.

Tauffenberger A et al. (2013) Hum Mol Genet "Reduction of polyglutamine toxicity by TDP-43, FUS and progranulin in Huntington's disease models."

Bateman A, Parker JA, Tauffenberger A, Bennett HP, Chitramuthu BP

[Hum Mol Genet, 2013]

The DNA/RNA binding proteins TAR DNA-binding protein 43 (TDP-43) and fused-in-sarcoma (FUS) are genetically linked to amyotrophic lateral sclerosis and frontotemporal lobar dementia, while the inappropriate cytoplasmic accumulations of TDP-43 and FUS are observed in a growing number of late-onset pathologies including spinocerebellar ataxia 3, Alzheimer's and Huntington's diseases (HD). To investigate if TDP-43 and FUS contribute to neurodegenerative phenotypes, we turned to a genetically accessible Caenorhabditis elegans model of polyglutamine toxicity. In C. elegans, we observe that genetic loss-of-function mutations for nematode orthologs of TDP-43 or FUS reduced behavioral defects and neurodegeneration caused by huntingtin exon-1 with expanded polyglutamines. Furthermore, using striatal cells from huntingtin knock-in mice we observed that small interfering ribonucleic acid (siRNA) against TDP-43 or FUS reduced cell death caused by mutant huntingtin. Moreover, we found that TDP-43 and the survival factor progranulin (PGRN) genetically interact to regulate polyglutamine toxicity in C. elegans and mammalian cells. Altogether our data point towards a conserved function for TDP-43 and FUS in promoting polyglutamine toxicity and that delivery of PGRN may have therapeutic benefits.

Tauffenberger A et al. (2019) Cell Death Dis "Lactate and pyruvate promote oxidative stress resistance through hormetic ROS signaling."

Magistretti PJ, Almustafa S, Fiumelli H, Tauffenberger A

[Cell Death Dis, 2019]

L-lactate was long considered a glycolytic by-product but is now being recognized as a signaling molecule involved in cell survival. In this manuscript, we report the role of L-lactate in stress resistance and cell survival mechanisms using neuroblastoma cells (SH-SY5Y) as well as the C. elegans model. We observed that L-lactate promotes cellular defense mechanisms, including Unfolded Protein Response (UPR) and activation of nuclear factor erythroid 2-related factor 2 (NRF2), by promoting a mild Reactive Oxygen Species (ROS) burst. This increase in ROS triggers antioxidant defenses and pro-survival pathways, such as PI3K/AKT and Endoplasmic Reticulum (ER) chaperones. These results contribute to the understanding of the molecular mechanisms involved in beneficial effects of L-lactate, involving mild ROS burst, leading to activation of unfolded protein responses and detoxification mechanisms. We present evidence that this hormetic mechanism induced by L-lactate protects against oxidative stress in vitro and in vivo. This work contributes to the identification of molecular mechanisms, which could serve as targets for future therapeutic approaches for cell protection and aging-related disorders.

Tauffenberger A et al. (2013) Neurobiol Aging "Evaluation of longevity enhancing compounds against transactive response DNA-binding protein-43 neuronal toxicity."

Tauffenberger A, Parker JA, Julien C

[Neurobiol Aging, 2013]

In simple systems, lifespan can be extended by various methods including dietary restriction, mutations in the insulin/insulin-like growth factor (IGF) pathway or mitochondria among other processes. It is widely held that the mechanisms that extend lifespan may be adapted for diminishing age-associated pathologies. We tested whether a number of compounds reported to extend lifespan in C. elegans could reduce age-dependent toxicity caused by mutant TAR DNA-binding protein-43 in C. elegans motor neurons. Only half of the compounds tested show protective properties against neurodegeneration, suggesting that extended lifespan is not a strong predictor for neuroprotective properties. We report here that resveratrol, rolipram, reserpine, trolox, propyl gallate, and ethosuximide protect against mutant TAR DNA-binding protein-43 neuronal toxicity. Finally, of all the compounds tested, only resveratrol required daf-16 and sir-2.1 for protection, and ethosuximide showed dependence on daf-16 for its activity.

Fardghassemi Y et al. (2017) Dis Model Mech "Rescue of ATXN3 neuronal toxicity in C. elegans by chemical modification of ER stress."

Parker JA, Fardghassemi Y, Gosselin S, Tauffenberger A

[Dis Model Mech, 2017]

Background: Polyglutamine expansion diseases are a group of hereditary neurodegenerative disorders that develop when a CAG repeat in the causative genes are unstably expanded above a certain threshold. The expansion of trinucleotide CAG repeats cause hereditary adult-onset neurodegenerative disorders such as Huntington's disease, dentatorubral-pallidoluysian atrophy, spinobulbar muscular atrophy and multiple forms of spinocerebellar ataxia (SCA). The most common dominantly inherited spinocerebellar ataxia is the type 3 (SCA3) also known as Machado-Joseph disease (MJD), is an autosomal dominant, progressive neurological disorder. The gene causatively associated with MJD is ATXN3 Recent studies have shown that this gene modulates endoplasmic reticulum (ER) stress.Results: We generated transgenic C. elegans strains expressing human ATXN3 genes in motor neurons, and animals expressing mutant ATXN3-CAG89 alleles showed decreased lifespan, impaired movement, and rates of neurodegeneration greater than wild type ATXN3-CAG10 controls. We tested three neuroprotective compounds (methylene blue, guanabenz and salubrinal) believed to modulate ER stress and observed that these molecules rescued ATXN3-CAG89 phenotypes. Furthermore, these compounds required specific branches of ER unfolded protein response (UPR(ER)), reduced global ER and oxidative stress, as well as polyglutamine aggregation.Conclusions: We introduce novel C. elegans models for MJD based on the expression of full-length ATXN3 in a limited number of neurons. Using these models, we discovered that chemical modulation of the UPR(ER) reduced neurodegeneration and warrants investigation in mammalian models of MJD.

Aggad D et al. (2014) J Neurosci "TDP-43 toxicity proceeds via calcium dysregulation and necrosis in aging Caenorhabditis elegans motor neurons."

Veriepe J, Aggad D, Parker JA, Tauffenberger A

[J Neurosci, 2014]

Amyotrophic lateral sclerosis (ALS) is a heterogeneous disease with either sporadic or genetic origins characterized by the progressive degeneration of motor neurons. At the cellular level, ALS neurons show protein misfolding and aggregation phenotypes. Transactive response DNA-binding protein 43 (TDP-43) has recently been shown to be associated with ALS, but the early pathophysiological deficits causing impairment in motor function are unknown. Here we used Caenorhabditis elegans expressing mutant TDP-43(A315T) in motor neurons and explored the potential influences of calcium (Ca(2+)). Using chemical and genetic approaches to manipulate the release of endoplasmic reticulum (ER) Ca(2+)stores, we observed that the reduction of intracellular Ca(2+) ([Ca(2+)]i) rescued age-dependent paralysis and prevented the neurodegeneration of GABAergic motor neurons. Our data implicate elevated [Ca(2+)]i as a driver of TDP-43-mediated neuronal toxicity. Furthermore, we discovered that neuronal degeneration is independent of the executioner caspase CED-3, but instead requires the activity of the Ca(2+)-regulated calpain protease TRA-3, and the aspartyl protease ASP-4. Finally, chemically blocking protease activity protected against mutant TDP-43(A315T)-associated neuronal toxicity. This work both underscores the potential of the C. elegans system to identify key targets for therapeutic intervention and suggests that a focused effort to regulate ER Ca(2+) release and necrosis-like degeneration consequent to neuronal injury may be of clinical importance.

Vaccaro A et al. (2012) PLoS One "Mutant TDP-43 and FUS cause age-dependent paralysis and neurodegeneration in C. elegans."

Tauffenberger A, Drapeau P, Vaccaro A, Rouleau G, Parker JA, Aggad D

[PLoS One, 2012]

Mutations in the DNA/RNA binding proteins TDP-43 and FUS are associated with Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration. Intracellular accumulations of wild type TDP-43 and FUS are observed in a growing number of late-onset diseases suggesting that TDP-43 and FUS proteinopathies may contribute to multiple neurodegenerative diseases. To better understand the mechanisms of TDP-43 and FUS toxicity we have created transgenic Caenorhabditis elegans strains that express full-length, untagged human TDP-43 and FUS in the worm's GABAergic motor neurons. Transgenic worms expressing mutant TDP-43 and FUS display adult-onset, age-dependent loss of motility, progressive paralysis and neuronal degeneration that is distinct from wild type alleles. Additionally, mutant TDP-43 and FUS proteins are highly insoluble while wild type proteins remain soluble suggesting that protein misfolding may contribute to toxicity. Populations of mutant TDP-43 and FUS transgenics grown on solid media become paralyzed over 7 to 12 days. We have developed a liquid culture assay where the paralysis phenotype evolves over several hours. We introduce C. elegans transgenics for mutant TDP-43 and FUS motor neuron toxicity that may be used for rapid genetic and pharmacological suppressor screening.

Vaccaro A et al. (2012) PLoS Genet "TDP-1/TDP-43 regulates stress signaling and age-dependent proteotoxicity in Caenorhabditis elegans."

Parker JA, Ash PE, Carlomagno Y, Petrucelli L, Vaccaro A, Tauffenberger A

[PLoS Genet, 2012]

TDP-43 is a multifunctional nucleic acid binding protein linked to several neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia. To learn more about the normal biological and abnormal pathological role of this protein, we turned to Caenorhabditis elegans and its orthologue TDP-1. We report that TDP-1 functions in the Insulin/IGF pathway to regulate longevity and the oxidative stress response downstream from the forkhead transcription factor DAF-16/FOXO3a. However, although tdp-1 mutants are stress-sensitive, chronic upregulation of tdp-1 expression is toxic and decreases lifespan. ALS-associated mutations in TDP-43 or the related RNA binding protein FUS activate the unfolded protein response and generate oxidative stress leading to the daf-16-dependent upregulation of tdp-1 expression with negative effects on neuronal function and lifespan. Consistently, deletion of endogenous tdp-1 rescues mutant TDP-43 and FUS proteotoxicity in C. elegans. These results suggest that chronic induction of wild-type TDP-1/TDP-43 by cellular stress may propagate neurodegeneration and decrease lifespan.