Adaptive preconditioning in neurological diseases -­ therapeutic insights from proteostatic perturbations

International audienceIn neurological disorders, both acute and chronic neural stress can disrupt cellular proteostasis, resulting in the generation of pathological protein. However in most cases, neurons adapt to these proteostatic perturbations by activating a range of cellular protective and repair responses, thus maintaining cell function. These interconnected adaptive mechanisms comprise a 'proteostasis network' and include the unfolded protein response, the ubiquitin proteasome system and autophagy. Interestingly, several recent studies have shown that these adaptive responses can be stimulated by preconditioning treatments, which confer resistance to a subsequent toxic challenge - the phenomenon known as hormesis. In this review we discuss the impact of adaptive stress responses stimulated in diverse human neuropathologies including Parkinson´s disease, Wolfram syndrome, brain ischemia, and brain cancer. Further, we examine how these responses - and the molecular pathways they recruit - might be exploited for therapeutic gai

Energy coupling in soybean bacteroids

Biological dinitrogen fixation by Rhizobium spp. in the root nodules of leguminous plants such as soybean is of considerable agronomic importance. Biological dinitrogen fixation is ATP- and reductant-dependent; between 12 and 30 mol of ATP are required per mol of dinitrogen reduced [1]. All free-living rhizobia are aerobic although some strains will also grow anaerobically with nitrate as the terminal electron acceptor [2] ; ATP and reductant are generated during the oxidation of an exogenously supplied carbon source. In the bacteroids within the root nodule the exogenous carbon source (photosynthate) is derived from photosynthetic CO₂ fixation by the host plant. The identity of the carbon source(s) oxidised by the bacteroids in vivo has not yet been confirmed although sucrose is the major photosynthetic product translocated to the root nodules [3]. As dinitrogen fixation represents a drain on the photosynthetic supply [4,5] and since the supply of photosynthate is probably one of the major factors that limits dinitrogen fixation in the Rhizobium-legume symbiosis [6] a high efficiency of energy coupling within the bacteroids would minimise the amount of photosynthate required to be oxidised to supply the ATP and reductant necessary for dinitrogen fLxation. The number of sites of oxidative phosphorylation in the bacteroids is unknown although Laane et al. [7,8] have found respiration induced membrane energisation in R. leguminosarum bacteroids. We investigated both the capability of the bacteroids to oxidise a variety of carbon sources and the number of sites of oxidative phosphorylation (proton-translocating loops) in the bacteroids

Anaerobic growth and denitrification by Rhizobium japonicum and other rhizobia

The product of nitrate respiration in Rhizobium japonicum and a number of other rhizobia capable of anaerobic growth utilizing nitrate was N2O. No N2 or ammonia was formed. Nitrate reduction was linked to ATP formation during anaerobic but not during aerobic growth. Free-living rhizobia may remove fixed nitrogen from the soil by denitrification

Mutations of intermediate effect are responsible for adaptation in evolving Pseudomonas fluorescens populations

The fixation of a beneficial mutation represents the first step in adaptation, and the average effect of such mutations is therefore a fundamental property of evolving populations. It is nevertheless poorly characterized because the rarity of beneficial mutations makes it difficult to obtain reliable estimates of fitness. We obtained 68 genotypes each containing a single fixed beneficial mutation from experimental populations of Pseudomonas fluorescens, evolving in medium with serine as the sole carbon source and estimated the selective advantage of each by competition with the ancestor. The distribution of selection coefficients is modal and closely resembles the Weibull distribution. The average selection coefficient (2.1) and beneficial mutation rate (3.8×10(−8)) are high relative to previous studies, possibly because the ancestral population grows poorly in serine-limited medium. Our experiment suggests that the initial stages of adaptation to stressful environments will involve the substitution of mutations with large effect on fitness