Alzheimer-related protein APL-1 modulates lifespan through heterochronic gene regulation in Caenorhabditis elegans.
Alzheimer-related protein APL-1 modulates lifespan through heterochronic gene regulation in Caenorhabditis elegans.
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作者：
Ewald CY;Marfil V;Li C
阿尔茨海默病是一种与年龄相关的疾病。淀粉样前体蛋白(APP)的突变可能是阿尔茨海默病的病因或保护性疾病。两个功能冗余的APP样基因(APLP1/2)的存在使得APP在衰老过程中的生物学功能难以揭开。线虫线虫只有一个APP家族成员APL-1。在这里，我们评估了APL-1对线虫寿命的影响，发现APL-1的过表达对线虫寿命有组织特异性的影响。APL-1在神经元中的过表达导致寿命缩短，而APL-1在皮下组织中的过表达通过抑制异慢性转录因子LIN-14的功能来保持年轻而导致寿命延长。APL-1寿命的延长还需要通过FOXO转录因子DAF-16、热休克因子HSF-1和维生素D样核激素受体DAF-12进行信号传递。我们认为，增强APL-1在皮下组织中的表达，保留了异时性LIN-14基因网络的调节，通过DAF-16/FOXO和HSF-1促进身体组织的维护，促进健康衰老。我们的工作揭示了保守的APP相关蛋白质如何调节衰老的机制联系。
Alzheimer's disease (AD) is an age‐associated disease. Mutations in the amyloid precursor protein (APP) may be causative or protective of AD. The presence of two functionally redundant APP‐like genes (APLP1/2) has made it difficult to unravel the biological function of APP during aging. The nematode Caenorhabditis elegans contains a single APP family member, apl‐1. Here, we assessed the function of APL‐1 on C. elegans’ lifespan and found tissue‐specific effects on lifespan by overexpression of APL‐1. Overexpression of APL‐1 in neurons causes lifespan reduction, whereas overexpression of APL‐1 in the hypodermis causes lifespan extension by repressing the function of the heterochronic transcription factor LIN‐14 to preserve youthfulness. APL‐1 lifespan extension also requires signaling through the FOXO transcription factor DAF‐16, heat‐shock factor HSF‐1, and vitamin D‐like nuclear hormone receptor DAF‐12. We propose that reinforcing APL‐1 expression in the hypodermis preserves the regulation of heterochronic lin‐14 gene network to improve maintenance of somatic tissues via DAF‐16/FOXO and HSF‐1 to promote healthy aging. Our work reveals a mechanistic link of how a conserved APP‐related protein modulates aging.
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影响因子：
7.8
作者：
Ibanez-Ventoso, Carolina;Yang, Maocheng;Driscoll, Monica
通讯作者：
Driscoll, Monica
DOI：
10.1073/pnas.90.24.12045
发表时间：
1993-12-15
影响因子：
11.1
作者：
DAIGLE, I;LI, C
通讯作者：
LI, C
影响因子：
56.9
作者：
Boehm, M;Slack, F
通讯作者：
Slack, F
影响因子：
4.8
作者：
Hoopes, James T.;Liu, Xuying;Ha, Ya
通讯作者：
Ha, Ya
影响因子：
3.1
作者：
Ewald, Collin Y.;Li, Chris
通讯作者：
Li, Chris