Horrocks, J. | Search bioRxiv

bioRxiv2024

Neuronal CBP-1 is required for enhanced body muscle proteostasis in response to reduced translation downstream of mTOR

BackgroundThe ability to maintain muscle function decreases with age and loss of proteostatic function. Diet, drugs, and genetic interventions that restrict nutrients or nutrient signaling help preserve long-term muscle function and slow age-related decline. Previously, it was shown that attenuating protein synthesis downstream of the mechanistic target of rapamycin (mTOR) gradually increases expression of heat shock response (HSR) genes in a manner that correlates with increased resilience to protein unfolding stress. Here, we investigate the role of specific tissues in mediating the cytoprotective effects of low translation. MethodsThis study uses genetic tools (transgenic C. elegans, RNA interference and gene expression analysis) as well as physiological assays (survival and paralysis assays) in order to better understand how specific tissues contribute to adaptive changes involving cellular cross-talk that enhance proteostasis under low translation conditions. ResultsWe use the C. elegans system to show that lowering translation in neurons or the germline increases heat shock gene expression and survival under conditions of heat stress. In addition, we find that low translation in these tissues protects motility in a body muscle-specific model of proteotoxicity that results in paralysis. Low translation in neurons or germline also results in increased expression of certain muscle regulatory and structural genes, reversing reduced expression normally observed with aging in C. elegans. Enhanced resilience to protein unfolding stress requires neuronal expression of cbp-1. ConclusionLow translation in either neurons or the germline orchestrate protective adaptation in other tissues, including body muscle.

genetics↗

bioRxiv2024

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

Dietary restriction (DR) mitigates loss of proteostasis associated with aging that underlies neurodegenerative conditions including Alzheimers disease and related dementias. Previously, we observed increased translational efficiency of certain FMRFamide-like neuropeptide (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.

molecular biology↗