Mir Dilawar Ahmad, Cox Matthew, Horrocks Jordan, Ma Zhengxin, Rogers Aric
bioRxiv. 2024 Feb 8:2024.02.06.579250. doi: 10.1101/2024.02.06.579250.
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 neuropeptide ( ) genes and the neuroprotective growth factor progranulin gene under dietary restriction in . Here, we tested the effects of , , and 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 and 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 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 gene that showed increased thermotolerance compared to fully fed wild type animals demonstrated no change in thermotolerance in response to knockdown of or genes. Finally, we tested effects on motility in a neural-specific model of proteotoxicity and found that neuronal knockdown of and genes improved motility in early life regardless of diet. However, knocking these genes down in non-neuronal tissue had variable results. RNAi targeting increased motility by day seven of adulthood regardless of diet. Interestingly, non-neuronal RNAi of decreased motility under standard feeding conditions while DR increased motility for this gene knockdown by day seven (early mid-life). Results show that , , , and 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.
饮食限制（DR）可减轻与衰老相关的蛋白质稳态丧失，而这种丧失是包括阿尔茨海默病和相关痴呆症在内的神经退行性疾病的基础。此前，我们观察到在饮食限制条件下，秀丽隐杆线虫中某些类FMRF酰胺神经肽（ ）基因和神经保护生长因子颗粒蛋白前体基因的翻译效率有所提高。在此，我们测试了 、 、 和 在标准和饮食限制条件下对寿命和蛋白质稳态的影响。我们还根据它们在神经元或非神经元组织中的表达来测试和区分其功能。在三个实验中的两个实验里，在神经组织中选择性降低 和 基因的表达，发现在正常喂食条件下以及饮食限制条件下，生存率均无差异。在非神经元组织中降低 的表达显示寿命缩短，这并非饮食限制所特有的现象。关于蛋白质稳态，与完全喂食的野生型动物相比，因 基因突变而产生的饮食限制遗传模型表现出耐热性增加，在敲低 或 基因后，耐热性未发生变化。最后，我们在蛋白质毒性的神经特异性模型中测试了对运动能力的影响，发现无论饮食如何，在神经元中敲低 和 基因均可改善早期生活中的运动能力。然而，在非神经元组织中敲低这些基因则产生了不同的结果。无论饮食如何，靶向 的RNA干扰在成年期第7天增加了运动能力。有趣的是，在标准喂食条件下，对 进行非神经元RNA干扰会降低运动能力，而在饮食限制条件下，到成年期第7天（生命早期中期），这种基因敲低会增加运动能力。结果表明， 、 、 和 在与饮食相关的寿命变化或全身蛋白质稳态中没有主要作用。然而，在蛋白质毒性的神经特异性模型中，这些基因在神经元中的表达降低会在生命早期增加运动能力，而在相同条件下，非神经元表达的敲低大多会在中年期增加运动能力。
