Title: Understanding the cell non-autonomous control of proteostasis and its roles in ageing and neurodegenerative disease
Funder: Medical Research Council

Abstract: Many neurodegenerative diseases emerge late in life, making ageing the primary risk factor for a range of disorders including Alzheimer’s and Parkinson’s diseases. Ageing is associated with an increase in protein misfolding and aggregation, which is believed to underlie these age-onset neurodegenerations. One factor that may contribute to this increase in protein aggregation is a breakdown in cellular stress responses, mechanisms designed to detect and resolve stress-induced misfolding. One of these stress responses, the ER unfolded protein response (UPRER), monitors the folding of proteins within the secretory pathway. We have found that the ability to activate the UPRER declines with age, leading to a loss of resistance to stress in older animals, and that stress resistance can be rescued in older individuals by restoring this signaling pathway. Moreover, activating the UPRER only in neurons is sufficient to increase stress resistance and extend lifespan, suggesting that neurons play a critical role in protection from stress and that a loss of UPRER function in neurons may underlie aspects of ageing and disease development. We are now working to define the mechanisms underlying the loss of UPRER activation with age, and the role this plays in neurodegenerative disease. To do this we will use C. elegans models of neurodegeneration, in which disease-associated proteins are expressed in specific tissues, and activate the UPRER by expression of the activated transcription factor xbp-1s in these animals to determine whether onset and progression of aggregation and toxicity are modulated by UPRER activation. We will then express xbp1s in mouse models of Alzheimer’s disease to monitor effects on disease onset and outcomes. Our work has also identified a pathway by which UPRER activation in neurons can induce cell non-autonomous UPRER activation in distal tissues, a process that requires neuronal secretion and is essential for the beneficial effects of neuronal UPRER activation. Identifying the components of this pathway will help us to understand how neurons orchestrate whole-body physiological responses to environmental conditions, and give us the opportunity to manipulate this pathway for therapeutic purposes. We have used metabolomic, genetic and RNA-seq screening approaches to identify genes and molecules involved in this pathway, and will now characterize the specific roles of these candidate components. To do this we will use C. elegans reporter strains that allow us to detect UPRER activation in different tissues, so that we can determine whether gene expression or knockdown, or treatment with different signaling molecules, induces or inhibits non-autonomous UPRER activation. We can then manipulate these neuronal pathways to determine their effects on ageing and disease models. In addition, we will use reporter strains to see in which neurons the UPRER is activated under stress, and then express xbp-1s in those neurons, to find out which specific neurons and neuronal types are responsible for sending UPRER-activating signals. These approaches together will increase our understanding of the cell non-autonomous control of protein folding, and suggest new avenues for treatment of neurodegenerative disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL