Homeodomain-interacting protein kinase maintains neuronal homeostasis during normal Caenorhabditis elegans aging and systemically regulates longevity from serotonergic and GABAergic neurons.
Homeodomain-interacting protein kinase maintains neuronal homeostasis during normal Caenorhabditis elegans aging and systemically regulates longevity from serotonergic and GABAergic neurons.
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DOI：
10.7554/elife.85792
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发表时间：
2023-06-20
期刊：
影响因子：
7.7
通讯作者：
Samuelson AV
中科院分区：
文献类型：
--
作者：
Lazaro-Pena MI;Cornwell AB;Diaz-Balzac CA;Das R;Ward ZC;Macoretta N;Thakar J;Samuelson AV
蛋白质组的衰老和与年龄相关的下降部分是通过神经元对进化上保守的转录效应物的控制来决定的，这些转录效应物通过调节一个扩张的蛋白平衡网络来保护在波动的代谢和应激条件下的动态平衡。我们发现秀丽隐杆线虫同源结构域相互作用蛋白激酶(HPK-1)在衰老过程中作为一个关键的转录效应因子来维持神经元的完整性、功能和蛋白平衡。HPK-1的缺失导致神经元基因表达的严重失调，包括与神经元衰老相关的基因。在正常衰老期间，HPK-1在整个神经系统中的表达比任何其他激酶都更广泛地增加。在老化的神经系统中，HPK-1的诱导与关键的长寿转录因子重叠，这表明HPK-1的表达缓解了自然年龄相关的生理衰退。一直以来，泛神经元HPK-1的过度表达延长了寿命，保持了神经系统内外的蛋白稳定，并提高了应激抵抗能力。神经元型HPK-1通过激活蛋白激酶来改善蛋白平衡。Hpk-1在5-羟色胺能和γ-氨基丁酸能神经元中以非自主的方式发挥作用，通过特异性地调节蛋白平衡网络的不同成分来改善远端组织中的蛋白平衡。增加的5-羟色胺能HPK-1可增强热休克反应和急性应激的存活率。相反，GABA能的HPK-1诱导基础自噬并延长寿命，这需要MXL-2(MLX)、HLH-30(TFEB)和daf-16(FOXO)。我们的工作确立了HPK-1是一种关键的神经元转录调节因子，对于在衰老过程中保存神经元功能至关重要。此外，这些数据为神经系统如何通过维持机体内环境平衡来划分急性和慢性适应性反应途径以延缓衰老提供了新的见解。蛋白质对于维持健康生物体的几乎每一个细胞过程都是必不可少的。一个复杂的通路和信号分子网络调节蛋白质，使它们在一个被称为蛋白质平衡的过程中正确工作。随着身体的衰老，这个网络可能会受到破坏，从而导致产生有缺陷的蛋白质。许多蛋白质最终被错误折叠--换句话说，它们在分子水平上畸形，这对细胞可能是有毒的。这种错误折叠的蛋白质的积聚与几种神经系统疾病有关，包括阿尔茨海默氏症、帕金森氏症和亨廷顿病。细胞有不同的方式来检测和响应内部应激源，如组织或器官损伤。例如，当检测到损伤时，神经系统中的特定蛋白质可以发出“中枢”警报，然后启动并协调身体系统对外围细胞和组织做出反应。但这究竟是如何发生的仍不清楚。为了更多地了解应激反应的中枢协调，Lazaro-Pena等人进行了研究。研究了一种这样的传感器蛋白，称为HPK-1，存在于线虫体内。他们首先在各种组织中过度表达了这种蛋白质。这表明，只有当HPK-1在神经组织中过度活跃时，它才能保护蛋白质，延长蠕虫的寿命。HPK-1含量的增加改善了蠕虫的健康寿命，较老的蠕虫也移动得更好。然而，神经细胞中缺乏HPK-1的基因操纵的蠕虫显示，随着年龄的增长，神经系统健康下降的速度更快，一旦HPK-1再次激活，这种情况可能会逆转。Lazaro-Pena等人。然后测量了不同生命阶段蠕虫体内HPK-1的含量。这表明，随着蠕虫年龄的增长，神经细胞中HPK-1的数量增加。HPK-1水平升高的神经细胞与与长寿相关的蛋白质表达增加重叠。此外，当HPK-1过表达时，它会刺激其他细胞信号的释放，从而触发保护性反应，以防止蛋白质的错误折叠和聚集，并帮助降解受损的蛋白质。这项研究首次表明，HPK-1似乎在正常衰老过程中发挥了保护作用，它可能是刺激其他保护机制的关键开关。这些发现可能会为神经系统如何协调许多不同的压力反应，并最终延缓全身衰老提供新的见解。
Aging and the age-associated decline of the proteome is determined in part through neuronal control of evolutionarily conserved transcriptional effectors, which safeguard homeostasis under fluctuating metabolic and stress conditions by regulating an expansive proteostatic network. We have discovered the Caenorhabditis elegans homeodomain-interacting protein kinase (HPK-1) acts as a key transcriptional effector to preserve neuronal integrity, function, and proteostasis during aging. Loss of hpk-1 results in drastic dysregulation in expression of neuronal genes, including genes associated with neuronal aging. During normal aging hpk-1 expression increases throughout the nervous system more broadly than any other kinase. Within the aging nervous system, hpk-1 induction overlaps with key longevity transcription factors, which suggests that hpk-1 expression mitigates natural age-associated physiological decline. Consistently, pan-neuronal overexpression of hpk-1 extends longevity, preserves proteostasis both within and outside of the nervous system, and improves stress resistance. Neuronal HPK-1 improves proteostasis through kinase activity. HPK-1 functions cell non-autonomously within serotonergic and γ-aminobutyric acid (GABA)ergic neurons to improve proteostasis in distal tissues by specifically regulating distinct components of the proteostatic network. Increased serotonergic HPK-1 enhances the heat shock response and survival to acute stress. In contrast, GABAergic HPK-1 induces basal autophagy and extends longevity, which requires mxl-2 (MLX), hlh-30 (TFEB), and daf-16 (FOXO). Our work establishes hpk-1 as a key neuronal transcriptional regulator critical for preservation of neuronal function during aging. Further, these data provide novel insight as to how the nervous system partitions acute and chronic adaptive response pathways to delay aging by maintaining organismal homeostasis. Proteins are essential for nearly every cellular process to sustain a healthy organism. A complex network of pathways and signalling molecules regulates the proteins so that they work correctly in a process known as proteostasis. As the body ages, this network can become damaged, which leads to the production of faulty proteins. Many proteins end up being misfolded – in other words, they are misshapen on the molecular level, which can be toxic for the cell. A build-up of such misfolded proteins is implicated in several neurological conditions, including Alzheimer’s, Parkinson’s and Huntington’s disease. Cells have various ways to detect and respond to internal stressors, such as tissue or organ damage. For example, specific proteins in the nervous system can raise a ‘central’ alert when damage is detected, which then primes and coordinates the body’s systems to respond in the peripheral cells and tissues. But exactly how this happens is still unclear. To find out more about the central coordination of stress responses, Lazaro-Pena et al. studied one such sensor protein, called HPK-1, in the roundworm C. elegans. They first overexpressed the protein in various tissues. This revealed that only when HPK-1 was overactive in nerve tissue, it protected proteins and prolonged the lifespan of the worms. An increased amount of HPK-1 improved the health span of the worms and older worms also moved better. However, genetically manipulated worms lacking HPK-1 in their nerve cells showed a faster decline in nervous system health as they aged, which could be reversed once HPK-1 was activated again. Lazaro-Pena et al. then measured the amount of HPK-1 in worms at different stages of their life. This showed that as the worms aged, the amount of HPK-1 increased in the nerve cells. The nerve cells in which HPK-1 levels increased overlapped with an increased expression of proteins associated with longevity. Moreover, when HPK-1 was overexpressed, it stimulated the release of other cell signals, which then triggered protective responses to prevent the misfolding and aggregation of proteins and to help degrade damaged proteins. This study shows for the first time that HPK-1 appears to play a protective role during normal ageing and that it may act as a key switch to stimulate other protective mechanisms. These findings may give rise to new insights into how the nervous system can coordinate many different stress responses, and ultimately delay ageing throughout the whole body.
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影响因子：
9.8
作者：
Walter L;Baruah A;Chang HW;Pace HM;Lee SS
通讯作者：
Lee SS
影响因子：
5.8
作者：
Suriyalaksh M;Raimondi C;Mains A;Segonds-Pichon A;Mukhtar S;Murdoch S;Aldunate R;Krueger F;Guimerà R;Andrews S;Sales-Pardo M;Casanueva O
通讯作者：
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影响因子：
1.2
作者：
Lazaro-Pena, Maria, I;Cornwell, Adam B.;Samuelson, Andrew, V
通讯作者：
Samuelson, Andrew, V
通过钙依赖性调节热休克反应对蛋白质稳态的神经元重编程。
影响因子：
4.5
作者：
Silva MC;Amaral MD;Morimoto RI
通讯作者：
Morimoto RI