Herbert Alan
Discovery, InsideOutBio, Charlestown, MA, USA.
Neurosci Insights. 2025 Jun 6;20:26331055251338815. doi: 10.1177/26331055251338815. eCollection 2025.
Our memories are almost magical. We can experience an event for a short moment in time and quickly recall it decades later. This review explores the impact of some relatively new discoveries in the field of flipon biology that provide insight into diseases associated with impaired memory function. I examine how an ancient immune system based on Z-DNA and Z-RNA (collectively called ZNAs) regulates pathways that impact the memories modeled by synapses. The outcomes depend on intracellular defenses activated by endogenous retroelements (ERE) and virus, and on extracellular responses to ZNAs in bacterial biofilms. The bacterial amyloids and complement activation pathways further exacerbate the decline of cognitive and affective functions by inducing remodeling of synapses. In addition to immune EREs, a class of memory EREs potentially acts as ribotransmitters. These RNAs are transported across the synapse to program the connections between neurons that underlie the formation and remodeling of memories. Examples exist of ribotransmitters derived from ERE transcripts and assembled into capsids capable of transsynaptic transmission. In contrast, the immune EREs protect the nervous system by dismantling synapses to prevent viruses and retrotransposons from crossing them. The complexity of the interactions between memory and immune EREs likely give rise to the inverted U-shaped dose-response curves for the therapeutics currently available to treat cognitive decline. Other approaches for disease prevention are suggested, along with those that promote the regeneration and reprogramming of neuronal circuits.
我们的记忆几乎具有魔力。我们能在短时间内经历某一事件，并在几十年后迅速回忆起它。本综述探讨了翻转子生物学领域一些相对较新的发现所产生的影响，这些发现为与记忆功能受损相关的疾病提供了见解。我研究了基于Z-DNA和Z-RNA（统称为ZNA）的古老免疫系统如何调节影响由突触塑造的记忆的通路。结果取决于内源性逆转录元件（ERE）和病毒激活的细胞内防御，以及对细菌生物膜中ZNA的细胞外反应。细菌淀粉样蛋白和补体激活途径通过诱导突触重塑进一步加剧认知和情感功能的衰退。除了免疫ERE，一类记忆ERE可能作为核糖传递体发挥作用。这些RNA被转运穿过突触，为构成记忆形成和重塑基础的神经元之间的连接进行编程。存在源自ERE转录本并组装成能够进行跨突触传递的衣壳的核糖传递体实例。相比之下，免疫ERE通过拆解突触来保护神经系统，以防止病毒和逆转座子穿过它们。记忆和免疫ERE之间相互作用的复杂性可能导致目前用于治疗认知衰退的疗法出现倒U形剂量反应曲线。文中还提出了其他疾病预防方法，以及促进神经回路再生和重编程的方法。
