Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037.
Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, La Jolla, CA 92037.
Proc Natl Acad Sci U S A. 2018 Aug 14;115(33):E7710-E7719. doi: 10.1073/pnas.1801117115. Epub 2018 Jul 30.
Cell-autonomous and cell-nonautonomous mechanisms of neurodegeneration appear to occur in the proteinopathies, including Alzheimer's and Parkinson's diseases. However, how neuronal toxicity is generated from misfolding-prone proteins secreted by nonneuronal tissues and whether modulating protein aggregate levels at distal locales affects the degeneration of postmitotic neurons remains unknown. We generated and characterized animal models of the transthyretin (TTR) amyloidoses that faithfully recapitulate cell-nonautonomous neuronal proteotoxicity by expressing human TTR in the muscle. We identified sensory neurons with affected morphological and behavioral nociception-sensing impairments. Nonnative TTR oligomer load and neurotoxicity increased following inhibition of TTR degradation in distal macrophage-like nonaffected cells. Moreover, reducing TTR levels by RNAi or by kinetically stabilizing natively folded TTR pharmacologically decreased TTR aggregate load and attenuated neuronal dysfunction. These findings reveal a critical role for modulation of aggregation-prone degradation that directly affects postmitotic tissue degeneration observed in the proteinopathies.
在蛋白构象疾病（包括阿尔茨海默病和帕金森病）中，似乎存在细胞自主和非细胞自主的神经退行性变机制。然而，由非神经元组织分泌的易错误折叠蛋白产生的神经元毒性，以及调节远距离局部的蛋白聚集体水平是否会影响有丝分裂后神经元的变性，目前仍不清楚。我们生成并表征了转甲状腺素蛋白（TTR）淀粉样变性的动物模型，通过在肌肉中表达人 TTR，忠实地再现了非细胞自主的神经元蛋白毒性。我们发现感觉神经元的形态和行为痛觉感知受损。在远处非受影响的巨噬样细胞中抑制 TTR 降解后，非天然 TTR 寡聚物负荷和神经毒性增加。此外，通过 RNAi 或通过药物动力学稳定天然折叠的 TTR 降低 TTR 水平，可减少 TTR 聚集体负荷并减轻神经元功能障碍。这些发现揭示了对易聚集降解的调节在直接影响蛋白构象疾病中观察到的有丝分裂后组织变性方面的关键作用。
