The deposition of aggregated proteins is a common neuropathological denominator for neurodegenerative disorders. Experimental evidence suggests that disease propagation involves prion-like mechanisms that cause the spreading of template-directed aggregation of specific disease-associated proteins. In transgenic (Tg) mouse models of superoxide dismutase-1 (SOD1)-linked amyotrophic lateral sclerosis (ALS), inoculation of minute amounts of human SOD1 (hSOD1) aggregates into the spinal cord or peripheral nerves induces premature ALS-like disease and template-directed hSOD1 aggregation that spreads along the neuroaxis. This infectious nature of spreading pathogenic aggregates might have implications for the safety of laboratory and medical staff, recipients of donated blood or tissue, or possibly close relatives and caregivers. Here we investigate whether transmission of ALS-like disease is unique to the spinal cord and peripheral nerve inoculations or if hSOD1 aggregation might spread from the periphery into the central nervous system (CNS). We inoculated hSOD1 aggregate seeds into the peritoneal cavity, hindlimb skeletal muscle or spinal cord of adult Tg mice expressing mutant hSOD1. Although we used up to 8000 times higher dose—compared to the lowest dose transmitting disease in spinal cord inoculations—the peripheral inoculations did not transmit seeded aggregation to the CNS or premature ALS-like disease in hSOD1 Tg mice. Nor was any hSOD1 aggregation detected in the liver, kidney, skeletal muscle or sciatic nerve. To explore potential reasons for the lack of disease transmission, we examined the stability of hSOD1 aggregates and found them to be highly vulnerable to both proteases and detergent. Our findings suggest that exposed individuals and personnel handling samples from ALS patients are at low risk of any potential transmission of seeded hSOD1 aggregation.

中文翻译：

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SOD1 聚集体的外周给药不会将致病性聚集体传递到 SOD1 转基因小鼠的中枢神经系统

聚集蛋白的沉积是神经退行性疾病的常见神经病理学分母。实验证据表明，疾病传播涉及类似朊病毒的机制，该机制导致特定疾病相关蛋白的模板导向聚集的传播。在超氧化物歧化酶-1 (SOD1) 相关的肌萎缩侧索硬化 (ALS) 的转基因 (Tg) 小鼠模型中，接种微量的人类 SOD1 (hSOD1) 聚集到脊髓或周围神经中会诱发早产的 ALS 样疾病和模板-定向的 hSOD1 聚集沿神经轴扩散。传播致病性聚集物的这种传染性可能对实验室和医务人员、捐赠血液或组织的接受者或可能的近亲和护理人员的安全产生影响。在这里，我们调查了 ALS 样疾病的传播是否是脊髓和周围神经接种所独有的，或者 hSOD1 聚集是否可能从周围扩散到中枢神经系统 (CNS)。我们将 hSOD1 聚合种子接种到表达突变 hSOD1 的成年 Tg 小鼠的腹腔、后肢骨骼肌或脊髓中。尽管与脊髓接种中传播疾病的最低剂量相比，我们使用了高达 8000 倍的剂量，但在 hSOD1 Tg 小鼠中，外周接种并未将种子聚集传播到 CNS 或过早的 ALS 样疾病。在肝脏、肾脏、骨骼肌或坐骨神经中也未检测到任何 hSOD1 聚集。为探索缺乏疾病传播的潜在原因，我们检查了 hSOD1 聚集体的稳定性，发现它们对蛋白酶和去污剂都非常脆弱。我们的研究结果表明，暴露于 ALS 患者样本的个人和人员发生种子 hSOD1 聚集的任何潜在传播的风险较低。