Institute of Neuropathology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
Department of Molecular Neuroscience, Weizmann Institute of Science, Rehovot, Israel.
PLoS Pathog. 2024 Sep 11;20(9):e1012552. doi: 10.1371/journal.ppat.1012552. eCollection 2024 Sep.
In prion diseases (PrDs), aggregates of misfolded prion protein (PrPSc) accumulate not only in the brain but also in extraneural organs. This raises the question whether prion-specific pathologies arise also extraneurally. Here we sequenced mRNA transcripts in skeletal muscle, spleen and blood of prion-inoculated mice at eight timepoints during disease progression. We detected gene-expression changes in all three organs, with skeletal muscle showing the most consistent alterations. The glutamate-ammonia ligase (GLUL) gene exhibited uniform upregulation in skeletal muscles of mice infected with three distinct scrapie prion strains (RML, ME7, and 22L) and in victims of human sporadic Creutzfeldt-Jakob disease. GLUL dysregulation was accompanied by changes in glutamate/glutamine metabolism, leading to reduced glutamate levels in skeletal muscle. None of these changes were observed in skeletal muscle of humans with amyotrophic lateral sclerosis, Alzheimer's disease, or dementia with Lewy bodies, suggesting that they are specific to prion diseases. These findings reveal an unexpected metabolic dimension of prion infections and point to a potential role for GLUL dysregulation in the glutamate/glutamine metabolism in prion-affected skeletal muscle.
在朊病毒病（PrD）中，错误折叠的朊病毒蛋白（PrPSc）的聚集体不仅在大脑中积累，而且在神经外器官中积累。这就提出了一个问题，即朊病毒特异性病理学是否也会在神经外发生。在这里，我们在疾病进展的八个时间点对感染朊病毒的小鼠的骨骼肌、脾脏和血液中的 mRNA 转录本进行了测序。我们在所有三个器官中都检测到了基因表达的变化，其中骨骼肌的变化最为一致。三种不同的瘙痒性朊病毒株（RML、ME7 和 22L）感染的小鼠和人类散发性克雅氏病患者的骨骼肌中，谷氨酸-氨连接酶（GLUL）基因均表现出一致的上调。GLUL 失调伴随着谷氨酸/谷氨酰胺代谢的改变，导致骨骼肌中谷氨酸水平降低。在患有肌萎缩性侧索硬化症、阿尔茨海默病或路易体痴呆症的人类的骨骼肌中未观察到这些变化，这表明它们是朊病毒病特有的。这些发现揭示了朊病毒感染的一个意想不到的代谢维度，并指出 GLUL 失调在受朊病毒影响的骨骼肌中的谷氨酸/谷氨酰胺代谢中可能发挥作用。
