Chromatin modifiers MET-2 and SET-25 are required for behavioural and molecular inheritance after early-life toxic stress in C. elegans

Stress exposure early in life is associated with behavioural and bodily changes that can develop several neuropsychiatric illnesses such as dementia. Experiences during the critical perinatal period form permanent, imprinted memories that can persistently alter expression levels of key genes through epigenetic marking, which can underpin changes in behaviour, molecular and stress responsivity throughout later life, including the next generations. Besides, this implies that gene by environment interactions (such as through epigenetic modifications) may be involved in the onset of these phenotypes. Although there are a number of studies in this field, there are still research gaps. For this reason, understanding the molecular mechanisms underlying the enduring effects of early-life stress is an important research area of the neuroscience. The aim of this project is to determine the behavioural and molecular changes and if there are changes in the epigenetic enzymes that can explain in part this phenomenon. Here using an experimental paradigm, we report that in response to early-life stresses, Caenorhabditis elegans nematodes form an imprinted behavioural and cellular defence memory. We show that exposing newly-born worms to toxic antimycin A exposure or repeated exposure, promotes aversive behaviour through chemotaxis assay and stimulates the expression of the hsp-6 enzyme a toxinspecific cytoprotective. Learned adult defences require memory formation during the L1 larval stage and do not appear to confer increased protection against the toxin. We found that aversive behaviour is inherited only to the F1 generation after 1 exposure to the toxic or can be passed to the F4 generation after 4 exposures to the toxic. At the molecular level, we found changes in the chromatin modifiers MET-2 and SET-25 as well as their target gene SKN-1 until the F3 generation after 1 exposure to the toxic or until the F5 generation after 4 exposures to the toxic stress. Furthermore, we found changes in the lifespan after 1 exposure in the F1 until F3 generations as well as in the F1 until F5 generations after 4 exposures to the toxic stimulus. Regarding the oxidative stress response, we found changes in the same generations after 1 exposure or after 4 exposures to early life toxic stress. Thus, exposure of Caenorhabditis elegans to toxic stresses in the critical period elicits adaptive behavioural and cytoprotective responses as we all as promote changes in the health outcomes, demonstrating a wide range of alterations that can appear after an early-life harmful stimulus. Likewise, we can conclude that these results are orchestrated by SET-25 pathway through SKN-1 transcription factor, which forms imprinted aversive behaviour and imprints a cytoprotective memory in the adulthood and the successive generations. These results, open a new avenue for new epigenetic therapies for neuropsychiatric disorders through chromati

Modelling the Role of the Hsp70/Hsp90 System in the Maintenance of Protein Homeostasis

Neurodegeneration is an age-related disorder which is characterised by the accumulation of aggregated protein and neuronal cell death. There are many different neurodegenerative diseases which are classified according to the specific proteins involved and the regions of the brain which are affected. Despite individual differences, there are common mechanisms at the sub-cellular level leading to loss of protein homeostasis. The two central systems in protein homeostasis are the chaperone system, which promotes correct protein folding, and the cellular proteolytic system, which degrades misfolded or damaged proteins. Since these systems and their interactions are very complex, we use mathematical modelling to aid understanding of the processes involved. The model developed in this study focuses on the role of Hsp70 (IPR00103) and Hsp90 (IPR001404) chaperones in preventing both protein aggregation and cell death. Simulations were performed under three different conditions: no stress; transient stress due to an increase in reactive oxygen species; and high stress due to sustained increases in reactive oxygen species. The model predicts that protein homeostasis can be maintained during short periods of stress. However, under long periods of stress, the chaperone system becomes overwhelmed and the probability of cell death pathways being activated increases. Simulations were also run in which cell death mediated by the JNK (P45983) and p38 (Q16539) pathways was inhibited. The model predicts that inhibiting either or both of these pathways may delay cell death but does not stop the aggregation process and that eventually cells die due to aggregated protein inhibiting proteasomal function. This problem can be overcome if the sequestration of aggregated protein into inclusion bodies is enhanced. This model predicts responses to reactive oxygen species-mediated stress that are consistent with currently available experimental data. The model can be used to assess specific interventions to reduce cell death due to impaired protein homeostasis

Modelling the molecular mechanisms of ageing

This document is the Accepted Manuscript version of a published work that appeared in final form in Bioscience reports. To access the final edited and published work see http://www.bioscirep.org/content/37/1/BSR20160177.The ageing process is driven at the cellular level by random molecular damage which slowly accumulates with age. Although cells possess mechanisms to repair or remove damage, they are not 100% efficient and their efficiency declines with age. There are many molecular mechanisms involved and exogenous factors such as stress also contribute to the ageing process. The complexity of the ageing process has stimulated the use of computational modelling in order to increase our understanding of the system, test hypotheses and make testable predictions. As many different mechanisms are involved, a wide range of models have been developed. This paper gives an overview of the types of models that have been developed, the range of tools used, modelling standards, and discusses many specific examples of models which have been grouped according to the main mechanisms that they address. We conclude by discussing the opportunities and challenges for future modelling in this field