Rôle du métabolisme énergétique dans un contexte de vieillissement chez C. elegans

L’incidence constante des maladies liées à l’âge reflète un réel enjeu dans nos sociétés actuelles, principalement lorsqu’il est question des cas de cancers, d’accidents cérébraux et de maladies neurodégénératives. Ces désordres sont liés à l’augmentation de l’espérance de vie et à un vieillissement de la population. Les coûts, estimés en milliards de dollars, représentent des sommes de plus en plus importantes. Bien que les efforts déployés soient importants, aucun traitement n’a encore été trouvé. Les maladies neurodégénératives, telles que la maladie d’Alzheimer, de Parkinson, d’Huntington ou la sclérose latérale amyotrophique (SLA), caractérisées par la dégénérescence d’un type neuronal spécifique à chaque pathologie, représentent un défi important. Les mécanismes de déclenchement de la pathologie sont encore nébuleux, de plus il est maintenant clair que certains de ces désordres impliquent de nombreux gènes impliqués dans diverses voies de signalisation induisant le dysfonctionnement de processus biologiques importants, tel que le métabolisme. Dans nos sociétés occidentales, une problématique, directement lié à notre style de vie s’ajoute. L’augmentation des quantités de sucre et de gras dans nos diètes a amené à un accroissement des cas de diabètes de type II, d’obésité et de maladies coronariennes. Néanmoins, le métabolisme du glucose, principale source énergétique du cerveau, est primordial à la survie de n’importe quel organisme. Lors de ces travaux, deux études effectuées à l’aide de l’organisme Caenorhabditis elegans ont porté sur un rôle protecteur du glucose dans un contexte de vieillissement pathologique et dans des conditions de stress cellulaire. Le vieillissement semble accéléré dans un environnement enrichi en glucose. Cependant, les sujets traités ont démontré une résistance importante à différents stress et aussi à la présence de protéines toxiques impliquées dans la SLA et la maladie de Huntington. Dans un deuxième temps, nous avons démontré que ces effets peuvent aussi être transmis à la génération suivante. Un environnement enrichi en glucose a pour bénéfice de permettre une meilleure résistance de la progéniture, sans pour autant transmettre les effets néfastes dû au vieillissement accéléré.The constant increase of the cases of age-related diseases, including cancers, cerebral accidents and neurodegenerative diseases raises a real problem in our current societies. These disorders are very strongly linked to the increase of life expectancy and to the ageing population. The costs, estimated in billion dollars, requiring vast medical resources and very few treatments exist today. Neuronal diseases, such as the Alzheimer's, Parkinson’s, Huntington’s disease and amyotrophic lateral sclerosis (ALS) are characterized by the degeneration of various types of neurons. This represents an important challenge because besides the lack of understanding the underlying mechanisms related to their pathology, it is now clear that some of these disorders involve several genes and lead to the dysfunction of fundmental biological processes such as metabolism. In western societies lifestyle and dietary practices may contribute to disease. The increased quantities of sugar and fat in western diets are thought to contribute to the rise of metabolic disorders, including Type II diabetes, obesity and coronary diseases. Nevertheless, it is important to understand that the metabolism of glucose, the brain’s main energy source, is essential for survival. In this thesis, two studies using the model organism Caenorhabditis elegans investigated a potential protective role of the glucose in a context of pathological ageing and in conditions of cellular stress. Although ageing seems accelerated in a glucose enriched environment, the test subjects demonstrated an improved resistance to numerous stresses including against toxic proteins involved in the ALS and Huntington's disease. Secondly, it appeared that these effects can be heritably transmitted to successive generations of animals. Thus, a glucose enriched environment allows for increased stress resistance in the offspring, without transmitting the negative effects of accelerated ageing

The Strategic Location of Glycogen and Lactate: From Body Energy Reserve to Brain Plasticity

Brain energy metabolism has been the object of intense research in recent years. Pioneering work has identified the different cell types involved in energy production and use. Recent evidence has demonstrated a key role of L-Lactate in brain energy metabolism, producing a paradigm-shift in our understanding of the neuronal energy metabolism. At the center of this shift, is the identification of a central role of astrocytes in neuroenergetics. Thanks to their morphological characteristics, they are poised to take up glucose from the circulation and deliver energy substrates to neurons. Astrocyte neuron lactate shuttle (ANLS) model, has shown that the main energy substrate that astrocytes deliver to neurons is L-Lactate, to sustain neuronal oxidative metabolism. L-Lactate can also be produced from glycogen, the storage form of glucose, which is exclusively localized in astrocytes. Inhibition of glycogen metabolism and the ensuing inhibition of L-Lactate production leads to cognitive dysfunction. Experimental evidence indicates that the role of lactate in cognitive function relates not only to its role as a metabolic substrate for neurons but also as a signaling molecule for synaptic plasticity. Interestingly, a similar metabolic uncoupling appears to exist in peripheral tissues plasma, whereby glucose provides L-Lactate as the substrate for cellular oxidative metabolism. In this perspective article, we review the known information on the distribution of glycogen and lactate within brain cells, and how this distribution relates to the energy regime of glial vs. neuronal cells

Mutant TDP-43 and FUS Cause Age-Dependent Paralysis and Neurodegeneration in C. elegans

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

Using C. elegans to discover therapeutic compounds for ageing-associated neurodegenerative diseases

Age-associated neurodegenerative disorders such as Alzheimer’s disease are a major public health challenge, due to the demographic increase in the proportion of older individuals in society. However, the relatively few currently approved drugs for these conditions provide only symptomatic relief. A major goal of neurodegeneration research is therefore to identify potential new therapeutic compounds that can slow or even reverse disease progression, either by impacting directly on the neurodegenerative process or by activating endogenous physiological neuroprotective mechanisms that decline with ageing. This requires model systems that can recapitulate key features of human neurodegenerative diseases that are also amenable to compound screening approaches. Mammalian models are very powerful, but are prohibitively expensive for high-throughput drug screens. Given the highly conserved neurological pathways between mammals and invertebrates, Caenorhabditis elegans has emerged as a powerful tool for neuroprotective compound screening. Here we describe how C. elegans has been used to model various human ageing-associated neurodegenerative diseases and provide an extensive list of compounds that have therapeutic activity in these worm models and so may have translational potential

The Endoplasmic Reticulum Stress Response in Neuroprogressive Diseases: Emerging Pathophysiological Role and Translational Implications

The endoplasmic reticulum (ER) is the main cellular organelle involved in protein synthesis, assembly and secretion. Accumulating evidence shows that across several neurodegenerative and neuroprogressive diseases, ER stress ensues, which is accompanied by over-activation of the unfolded protein response (UPR). Although the UPR could initially serve adaptive purposes in conditions associated with higher cellular demands and after exposure to a range of pathophysiological insults, over time the UPR may become detrimental, thus contributing to neuroprogression. Herein, we propose that immune-inflammatory, neuro-oxidative, neuro-nitrosative, as well as mitochondrial pathways may reciprocally interact with aberrations in UPR pathways. Furthermore, ER stress may contribute to a deregulation in calcium homoeostasis. The common denominator of these pathways is a decrease in neuronal resilience, synaptic dysfunction and even cell death. This review also discusses how mechanisms related to ER stress could be explored as a source for novel therapeutic targets for neurodegenerative and neuroprogressive diseases. The design of randomised controlled trials testing compounds that target aberrant UPR-related pathways within the emerging framework of precision psychiatry is warranted

Transgenerational inheritance of resistance to oxidative stress.

<p>(A) N2 animals exposed to GE are highly resistant to juglone-induced lethality and this resistance was transmitted to descendent progeny in the F1 and generation, P<0.0001 versus untreated animals. (B–E) Resistance to oxidative stress by GE was lost in the P0 and F1 generations in animals mutant for (B) <i>daf-16</i>, (C) <i>aak-2</i>, or (D) <i>sir-2.1</i>. (E) GE continued to provide resistance to P0 and F1 animals mutant for <i>hif-1</i>, P<0.0001 versus untreated animals. (F) GE increased oxidative stress resistance in P0 N2 animals but this effect was lost in F1 animals treated with <i>daf-16</i>, <i>aak-2</i> or <i>sir-2.1</i> RNAi clones.</p

Transgenerational inheritance of glucose phenotypes requires H3K4me3 components.

<p>(A) N2 animals treated with 2% GE had an increased H3K4me3 mark and this effect was lost in subsequent generations. (B–C) GE delayed late onset paralysis in P0 but not in F1 generation of mTDP-43; <i>set-2(ok952)</i> (B) and mTDP-43; <i>wdr-5.1(ok1417)</i> (C) animals compared to untreated control and this protection was lost in F1 generation. (D–E) Stress resistance was increased in P0 but not in F1 generation of COMPASS (Complex Proteins Associated with Set1) mutants (D) <i>set-2(ok952)</i> and (E) <i>wdr-5.1(ok1417)</i>. (F–G) Total progeny numbers were reduced in P0 but not in F1 generations of (F) <i>set-2</i> and (G) <i>wdr-5.1</i> mutants.</p

Heritable Transmission of Stress Resistance by High Dietary Glucose in <i>Caenorhabditis elegans</i>

<div><p>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 <i>Caenorhabditis elegans</i> 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.</p></div

Parental exposure to glucose provides transgenerational protection against neurodegeneration.

<p>(A–B) GE reduces TDP-43 mediated age-dependent (A) paralysis, P<0.0001 versus untreated animals and (B) neurodegeneration in P0 animals and their F1 descendants, *P<0.0001 versus untreated animals.</p