Roles of Progranulin and FRamides in Neural Versus Non-Neural Tissues on Dietary Restriction-Related Longevity and Proteostasis in C. elegans.

Abstract

Dietary 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 neuro-Peptide (FLP) genes and the neuroprotective growth factor progranulin gene prgn-1 under dietary restriction in C. elegans. Here, we tested the effects of flp-5, flp-14, flp-15 and pgrn-1 on 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 of pgrn-1 and flp genes 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 of flp-14 in non-neuronal tissue showed decreased lifespan that was not specific to DR. With respect to proteostasis, a genetic model of DR from mutation of the eat-2 gene that showed increased thermotolerance compared to fully fed wild type animals demonstrated no change in thermotolerance in response to knockdown of pgrn-1 or flp genes. Finally, we tested effects on motility in a neural-specific model of proteotoxicity and found that neuronal knockdown of pgrn-1 and flp genes improved motility in early life regardless of diet. However, knocking these genes down in non-neuronal tissue had variable results. RNAi targeting flp-14 increased motility by day seven of adulthood regardless of diet. Interestingly, non-neuronal RNAi of pgrn-1 decreased motility under standard feeding conditions while DR increased motility for this gene knockdown by day seven (early mid-life). Results show that pgrn-1, flp-5, flp-14, and flp-15 do 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.