Department of Pathology, Case Western Reserve University, 2103 Cornell Road, Cleveland, OH 44106, USA.
Neurobiol Dis. 2012 Mar;45(3):930-8. doi: 10.1016/j.nbd.2011.12.012. Epub 2011 Dec 11.
Prion disease associated neurotoxicity is mainly attributed to PrP-scrapie (PrP(Sc)), the disease associated isoform of a normal protein, the prion protein (PrP(C)). Participation of other proteins and processes is suspected, but their identity and contribution to the pathogenic process is unclear. Emerging evidence implicates imbalance of brain iron homeostasis as a significant cause of prion disease-associated neurotoxicity. The underlying cause of this change, however, remains unclear. We demonstrate that iron is sequestered in heat and SDS-stable protein complexes in sporadic-Creutzfeldt-Jakob-disease (sCJD) brains, creating a phenotype of iron deficiency. The underlying cause is change in the characteristics of ferritin, an iron storage protein that becomes aggregated, detergent-insoluble, and partitions with denatured ferritin using conventional methods of ferritin purification. A similar phenotype of iron deficiency is noted in the lumbar spinal cord (SC) tissue of scrapie infected hamsters, a site unlikely to be affected by massive neuronal death and non-specific iron deposition. As a result, the iron uptake protein transferrin (Tf) is upregulated in scrapie infected SC tissue, and increases with disease progression. A direct correlation between Tf and PrP(Sc) suggests sequestration of iron in dysfunctional ferritin that either co-aggregates with PrP(Sc) or is rendered dysfunctional by PrP(Sc) through an indirect process. Surprisingly, amplification of PrP(Sc)in vitro by the protein-misfolding-cyclic-amplification (PMCA) reaction using normal brain homogenate as substrate does not increase the heat and SDS-stable pool of iron even though both PrP(Sc) and ferritin aggregate by this procedure. These observations highlight important differences between PrP(Sc)-protein complexes generated in vivo during disease progression and in vitro by the PMCA reaction, and the significance of these complexes in PrP(Sc)-associated neurotoxicity.
朊病毒病相关性神经毒性主要归因于 PrP 淀粉样蛋白（PrP(Sc)），这是一种正常蛋白质——朊病毒蛋白（PrP(C)）的疾病相关异构体。其他蛋白质和过程的参与也被怀疑，但它们的身份和对致病过程的贡献尚不清楚。新出现的证据表明，脑铁平衡失衡是朊病毒病相关性神经毒性的一个重要原因。然而，这种变化的根本原因尚不清楚。我们证明，铁在散发性克雅氏病（sCJD）大脑中被热和 SDS 稳定的蛋白质复合物隔离，从而产生铁缺乏表型。其根本原因是铁储存蛋白——铁蛋白的特性发生变化，铁蛋白变得聚集，去污剂不溶，并且使用铁蛋白纯化的常规方法与变性铁蛋白一起分离。在感染瘙痒病的仓鼠的腰椎脊髓（SC）组织中也观察到类似的铁缺乏表型，这个部位不太可能受到大量神经元死亡和非特异性铁沉积的影响。因此，转铁蛋白（Tf）在感染瘙痒病的 SC 组织中上调，并且随着疾病的进展而增加。Tf 与 PrP(Sc)之间的直接相关性表明，铁被隔离在功能失调的铁蛋白中，这些铁蛋白要么与 PrP(Sc)共同聚集，要么通过间接过程被 PrP(Sc)使功能失调。令人惊讶的是，使用正常脑匀浆作为底物的蛋白质错误折叠循环扩增（PMCA）反应在体外扩增 PrP(Sc)时，即使 PrP(Sc)和铁蛋白通过该程序聚集，也不会增加热和 SDS 稳定的铁池。这些观察结果突出了在疾病进展过程中体内产生的 PrP(Sc)-蛋白质复合物与 PMCA 反应体外产生的 PrP(Sc)-蛋白质复合物之间的重要差异，以及这些复合物在 PrP(Sc)相关神经毒性中的意义。
