Roles of progranulin and FRamides in neural versus non-neural tissues on dietary restriction-related longevity and proteostasis inC. elegans

Abstract

AbstractDietary restriction (DR) mitigates loss of proteostasis associated with aging that underlies neurodegenerative conditions including Alzheimer’s disease and related dementias. Previously, we observed increased translational efficiency of certain FMRFamide-like neuropeptide (flp) genes and the neuroprotective growth factor progranulin geneprgn-1under dietary restriction inC. elegans. Here, we tested the effects offlp-5,flp-14,flp-15andpgrn-1on lifespan and proteostasis under both standard and dietary restriction conditions. We also tested and distinguished function based on their expression in either neuronal or non-neuronal tissue. Lowering the expression ofpgrn-1andflpgenes selectively in neural tissue showed no difference in survival under normal feeding conditions nor under DR in two out of three experiments performed. Reduced expression offlp-14in non-neuronal tissue showed decreased lifespan that was not specific to DR. With respect to proteostasis, a genetic model of DR from mutation of theeat-2gene that showed increased thermotolerance compared to fully fed wild type animals demonstrated no change in thermotolerance in response to knockdown ofpgrn-1orflpgenes. Finally, we tested effects on motility in a neural-specific model of proteotoxicity and found that neuronal knockdown ofpgrn-1andflpgenes improved motility in early life regardless of diet. However, knocking these genes down in non-neuronal tissue had variable results. RNAi targetingflp-14increased motility by day seven of adulthood regardless of diet. Interestingly, non-neuronal RNAi ofpgrn-1decreased motility under standard feeding conditions while DR increased motility for this gene knockdown by day seven (early mid-life). Results show thatpgrn-1,flp-5,flp-14, andflp-15do not have major roles in diet-related changes in longevity or whole-body proteostasis. However, reduced expression of these genes in neurons increases motility early in life in a neural-specific model of proteotoxicity, whereas knockdown of non-neuronal expression mostly increases motility in mid-life under the same conditions.