We explored mechanisms involved in the age-dependent degeneration of human substantia nigra (SN) dopamine (DA) neurons. Owing to its important metabolic functions in post-mitotic neurons, we investigated the developmental and age-associated changes in the purine biosynthetic enzyme inosine monophosphate dehydrogenase (IMPDH). Tissue microarrays prepared from post-mortem samples of SN from 85 neurologically intact participants humans spanning the age spectrum were immunostained for IMPDH combined with other proteins. SN DA neurons contained two types of IMPDH structures: cytoplasmic IMPDH filaments and intranuclear IMPDH inclusions. The former were not age-restricted and may represent functional units involved in sustaining purine nucleotide supply in these highly metabolically active cells. The latter showed age-associated changes, including crystallization, features reminiscent of pathological inclusion bodies, and spatial associations with Marinesco bodies; structures previously associated with SN neuron dysfunction and death. We postulate dichotomous roles for these two subcellularly distinct IMPDH structures and propose a nucleus-based model for a novel mechanism of SN senescence that is independent of previously known neurodegeneration-associated proteins.

中文翻译：

---

肌苷单磷酸脱氢酶核内包涵体是人类黑质衰老和神经元应激的标志物

我们探索了人类黑质 (SN) 多巴胺 (DA) 神经元年龄依赖性变性的机制。由于其在有丝分裂后神经元中的重要代谢功能，我们研究了嘌呤生物合成酶肌苷单磷酸脱氢酶（IMPDH）的发育和年龄相关变化。从 85 名跨年龄段、神经系统完整的参与者的死后 SN 样本中制备组织微阵列，并与其他蛋白质结合进行 IMPDH 免疫染色。 SN DA 神经元含有两种类型的 IMPDH 结构：细胞质 IMPDH 丝和核内 IMPDH 包涵体。前者不受年龄限制，可能代表参与维持这些高度代谢活跃的细胞中嘌呤核苷酸供应的功能单位。后者表现出与年龄相关的变化，包括结晶、让人想起病理包涵体的特征以及与 Marinesco 小体的空间关联；先前与 SN 神经元功能障碍和死亡相关的结构。我们假设这两种亚细胞不同的 IMPDH 结构具有二分作用，并提出了一种基于细胞核的 SN 衰老新机制模型，该机制独立于先前已知的神经退行性相关蛋白。