Taylor Caitlin A, Maor-Nof Maya, Metzl-Raz Eyal, Hidalgo Aaron, Yee Callista, Gitler Aaron D, Shen Kang
Department of Biology, Stanford University, Stanford, CA 94305, USA.
The Phil and Penny Knight Initiative for Brain Resilience, Stanford University, Stanford, CA, 94305 USA.
bioRxiv. 2024 Aug 22:2024.08.21.608176. doi: 10.1101/2024.08.21.608176.
Neurons are long-lived, terminally differentiated cells with limited regenerative capacity. Cellular stressors such as endoplasmic reticulum (ER) protein folding stress and membrane trafficking stress accumulate as neurons age and accompany age-dependent neurodegeneration. Current strategies to improve neuronal resilience are focused on using factors to reprogram neurons or targeting specific proteostasis pathways. We discovered a different approach. In an unbiased screen for modifiers of neuronal membrane trafficking defects, we unexpectedly identified a role for histone deacetylases (HDACs) in limiting cellular flexibility in choosing cellular pathways to respond to diverse types of stress. Genetic or pharmacological inactivation of HDACs resulted in improved neuronal health in response to ER protein folding stress and endosomal membrane trafficking stress in and mammalian neurons. Surprisingly, HDAC inhibition enabled neurons to activate latent proteostasis pathways tailored to the nature of the individual stress, instead of generalized transcriptional upregulation. These findings shape our understanding of neuronal stress responses and suggest new therapeutic strategies to enhance neuronal resilience.
神经元是寿命较长、终末分化的细胞，再生能力有限。随着神经元衰老，诸如内质网（ER）蛋白折叠应激和膜运输应激等细胞应激源会不断累积，并伴随着与年龄相关的神经退行性变。目前提高神经元恢复力的策略主要集中在利用因子对神经元进行重编程或靶向特定的蛋白质稳态途径。我们发现了一种不同的方法。在对神经元膜运输缺陷修饰因子的无偏筛选中，我们意外地发现组蛋白脱乙酰酶（HDACs）在限制细胞选择应对多种应激类型的细胞途径时的灵活性方面发挥作用。HDACs的基因或药理学失活可改善线虫和哺乳动物神经元对内质网蛋白折叠应激和内体膜运输应激的反应，从而使神经元健康状况得到改善。令人惊讶的是，HDAC抑制使神经元能够激活针对个体应激性质量身定制的潜在蛋白质稳态途径，而不是普遍的转录上调。这些发现改变了我们对神经元应激反应的理解，并提出了增强神经元恢复力的新治疗策略。
