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. (2010) Aging, Metabolism, Stress, Pathogenesis, and Small RNAs, Madison, WI "Glucose rescues age-dependent proteotoxicity in C.elegans"

Vaccaro A, Parker A, Tauffenberger A

[Aging, Metabolism, Stress, Pathogenesis, and Small RNAs, Madison, WI, 2010]

As the population shifts to an older demographic, it has become important to find new therapeutic ways to combat neurological disease. To model neurodegeneration we use a C. elegans model for Huntington's Disease (HD). HD is a late-onset fatal neurodegenerative disease caused by an expanded CAG trinucleotide repeat that codes for glutamine (Q), and is characterized by the intracellular accumulation of mutant proteins. Our transgenic C. elegans strains expressing normal (19Q) and expanded mutant (128Q) polyQ in mechanosensory neurons show a progressive and polyQ size dependent loss-of-mechanosensation and increased-aggregation phenotypes in vivo1. The difference between mutant (128Q) and controls (19Q) is easily distinguished and the effects of genetic and pharmacological modifiers can be rapidly derived from small populations of animals2. Disrupted metabolism is one of a number of mechanisms that may contribute to neurodegeneration. Indeed, conditions that reprogram metabolism like dietary restriction are active areas of investigation in efforts to identify new therapeutic targets. We have observed that opposite to the effects on organismal lifespan, excess glucose suppresses toxicity in worm models of proteotoxicity. Furthermore, many of the genes essential for glucose-mediated suppression of proteotoxicity are in common with genes required for dietary restriction. These data demonstrate that glucose enrichment and dietary restriction utilize many of the same genetic pathways with opposite metabolic endpoints both of which are beneficial in models of neurodegeneration. A summary of our recent data will be presented. 1.Parker, J.A. et al. Expanded polyglutamines in Caenorhabditis elegans cause axonal abnormalities and severe dysfunction of PLM mechanosensory neurons without cell death. Proc Natl Acad Sci U S A 98, 13318-23 (2001). 2.Parker, J.A. et al. Resveratrol rescues mutant polyglutamine cytotoxicity in nematode and mammalian neurons. Nat Genet 37, 349-50 (2005).

Tauffenberger, A. et al. (2017) International Worm Meeting "Lactate and Pyruvate influence longevity, stress resistance and neuronal physiology in C. elegans."

Fiumelli, H., Magisttreti, P.J., Mottier, L., Tauffenberger, A., Parker, J.A.

[International Worm Meeting, 2017]

The world population shifts to an older demographic and with it there is an increased incidence of age related disorders including neurodegenerative diseases. As it has become a necessity to find new therapeutics, we focus our research on the role of energy metabolism on neuronal physiology. Disrupted energy metabolism is one of a number of mechanisms that may contribute to neurodegeneration. Indeed, conditions that reprogram energy metabolism like dietary restriction are active areas of investigation in efforts to identify new therapeutic targets. We sought to investigate the role of energy metabolism in neuronal protection using nematode diet supplementation with L-lactate and pyruvate, two important glucose metabolites. Although pyruvate has been extensively described as the glycolysis end product and first intermediate of the citric acid cycle, lactate has only recently emerged as an important oxidative metabolite and potential signalling molecule. Indeed, it has been known for many years as the end product of anaerobic glycolysis, but recent work1-2 has unveiled its role as a major factor in neuronal plasticity and protection. We used the C. elegans model for both neuronal dysfunction (unc-47 mutant) and neurodegeneration (Amyotrophic Lateral Sclerosis - TDP-43). Both models mimic motor neuron dysfunction resulting in age-dependent paralysis. We performed different tests to measure aging rate and neuronal survival in nematode with supplemented diet and tried to identify signalling pathways using RNAi. Our preliminary results suggest that both lactate and pyruvate increase resistance to oxidative stress, but reduce lifespan at high concentration. Interestingly, lactate but not pyruvate is able to reduce age-onset paralysis, suggesting a different mechanism than oxidative metabolism. A summary of our results will be presented. 1) Pellerin L. and Magistretti PJ., 1994 2) Yang et al., 2014

Tauffenberger, A. et al. (2019) International Worm Meeting "Lactate and Pyruvate increase stress resistance and delay aging through ROS signaling."

Fiumelli, H., Magistretti, P., Tauffenberger, A.

[International Worm Meeting, 2019]

Aging is a major risk factor for late-onset neurological disorders such as Alzheimer and Huntington's disease. Reduced efficiency of energy metabolism is a common feature in aging and neurological disorders. Maintenance of intracellular homeostasis is especially important for maintenance of neuronal functions during intense cerebral activity and decreases with the onset of neurodegenerative disease. We observed that treatment with L-lactate increases resistance to oxidative stress (H2O2), both in vitro(SH-SY5Y cells) and in C. elegans. Using the in vitro cell cultures, we identified upregulated transcription of chaperones involved in Unfolded Protein Response in the ER (UPRER) and components of ROS detoxification mechanism in response to L-lactate. When C. elegans diet was supplemented with L-lactate or pyruvate, we observed an increased stress resistance and a delay in aging. The effect of lactate on lifespan in C.elegansrelied on the activation of proteostasis mechanisms identified in the cell lines, alike in the in vitro cell cultures. However, the specific genetic requirements for the beneficial effect of lactate differed for delay in aging or resilience to acute oxidative stress. These results suggest that lactate and pyruvate slow down aging and protect against cellular stress through a hormetic effect and stimulate cellular activity in both mammalian and nematode biological systems.

Tauffenberger A et al. (2010) Aging, Metabolism, Stress, Pathogenesis, and Small RNAs, Madison, WI "Translation frameshiftings as a new mechanism of toxicity for the expanded CAG diseases"

Parker A, Tauffenberger A

[Aging, Metabolism, Stress, Pathogenesis, and Small RNAs, Madison, WI, 2010]

The expansion of CAG trinucleotides coding for glutamine (polyGln) is the cause of at least nine late-onset neurodegenerative diseases. The expanded CAG (expCAG) diseases may have some pathogenic mechanisms in common as the disease threshold for all of these disorders is around 40 CAG repeats and they display misfolded intracellular protein aggregation phenotypes. We have turned to the model organism C. elegans to explore mechanisms of expCAG toxicity Translational errors may be a major cause of disrupted protein homeostasis1, and mistranslation may be relevant to genes with expCAG tracts since frameshift errors to ([GCA]n) also produce expanded polyAlanine (polyAla). Large polyAla tracts are missing in the proteomes of almost all species compared to polyGln. The sequenced genome of H. sapiens revealed a low percentage of polyAla-containing genes (0.80%)2. Few proteins have 10-15 Ala residues and none with greater than 20 in the three species examined2. Experimental evidence suggests that expanded polyAla are intrinsically more toxic than polyGln3. Thus, over time mistranslation may be particularly harmful for the expCAG diseases since they result in polyGln/polyAla hybrids that may be more toxic than polyGln alone. Indeed, -1 frameshifting/mistranslation has been proposed as a novel mechanism of expCAG toxicity4. We are creating transgenic frameshift reporter strains expressing full-length ATXN3 protein, involved in Spinocerebellar Ataxia 3, the most common type of ataxia to investigate this phenomenon. Our model and a summary of our recent findings will be presented. 1.Drummond, D.A. & Wilke, C.O. Mistranslation-induced protein misfolding as a dominant constraint on coding-sequence evolution. Cell 134, 341-52 (2008). 2.Lavoie, H. et al. Polymorphism, shared functions and convergent evolution of genes with sequences coding for polyalanine domains. Hum Mol Genet 12, 2967-79 (2003). 3.Latouche, M. et al. Polyglutamine and polyalanine expansions in ataxin7 result in different types of aggregation and levels of toxicity. Mol Cell Neurosci 31, 438-45 (2006). .Gaspar, C. et al. CAG tract of MJD-1 may be prone to frameshifts causing polyalanine accumulation. Hum Mol Genet 9, 1957-66 (2000).

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.