Translational regulation downstream of nutrient sensing in a model of Alzheimer's-related proteotoxicity

项目摘要/增刊摘要

Project Summary/Abstract of Supplement The risk of protein misfolding diseases increases with age as mechanisms regulating proteostasis begin to fail. Age-associated neurodegenerative disorders are frequently characterized by unfolded proteins and aggregation, as observed in Alzheimer’s disease (AD) and related dementias (ADRD). Failure to maintain proper protein processing during aging is a major factor in pathology associated with these diseases. In the case of frontotemporal dementia (FTD), disease incidence increases in the presence of mutations in the progranulin gene GRN. All pathological GRN mutations result from reduced expression or function. Thus, methods of increasing GRN expression have the potential to help prevent or delay disease. Dietary restriction (DR) has been shown to improve maintenance of proteostasis and ameliorate disease outcomes in animal models. In preliminary data, we found that DR increases the translational efficiency of the neurotrophic factor GRN/pgrn-1. Higher levels of this factor are known to reverse proteotoxicity induced by TDP-43 and amyloid beta aggregates. Similar increases in translational efficiency are observed for FRamide neuropeptides, which are known in mammals to have roles in metabolism and stress response, but for which there is a lack of understanding about how they are regulated. Thus, while the associated parent grant is focused on the effects of DR and DR-associated low translation on body muscle and organismal physiology, this FTD/Alzheimer’s- focused administrative supplement (NOT-AG-20-008) specifically addresses how progranulin and these neurotransmitters are post-transcriptionally regulated under DR and DR-related low translation conditions. As part of our investigation into this form of gene regulation, we will also create new tools to investigate neuroprotection and the contribution of DR-related translational responses. Translation is an understudied area of gene regulation with the potential to yield new insights into neurodegeneration research. These studies will inform more time-consuming studies in mammalian systems and may yield new approaches with therapeutic potential. In addition, this research will lead to new avenues of exploration and will be used to develop future grant applications involving FTD and ADRD studies.