Mercer Robert C C, Le Nhat T T, Mirza-Romero Nadia, Flaherty Erin, Lavigna Giada, Orbe Isabel C, Gatdula Jean R P, Fraser Douglas G, Sundaravadivelu Aravind, Vultaggio Janelle S, Beeler Aaron B, Chiesa Roberto, Telling Glenn C, Harris David A
Boston University Chobanian & Avedisian School of Medicine, Department of Biochemistry & Cell Biology, Boston, Massachusetts, USA.
Department of Microbiology, Immunology, and Pathology, Prion Research Center, Colorado State University, Fort Collins, Colorado, USA.
bioRxiv. 2025 Jun 25:2025.06.24.661349. doi: 10.1101/2025.06.24.661349.
Prion diseases are fatal neurodegenerative diseases of humans and other mammals with no current treatment options. Here, we describe the characterization of a novel anti-prion compound, elacridar (GW120918), which has sub-micromolar activity in assays of prion infection, propagation and toxicity. Elacridar acts at an early step in the prion infection process, enhancing degradation of newly formed PrP. The lysosome is the likely site of elacridar's anti-prion effects, based on transcriptomic analysis and the use of functional lysosomal probes. Elacridar alters gene expression networks controlling lysosomal sterol and lipid metabolism but, unlike other lysosomotropic drugs, it prominently upregulates genes that control lysosomal pH. Surprisingly, these effects occur independently of TFEB nuclear translocation, suggesting novel regulatory mechanisms. The anti-prion effects of elacridar extend to α-synuclein and tau prions, highlighting lysosomal enhancement as a general strategy for the treatment of protein misfolding neurodegenerative diseases.
朊病毒病是人类和其他哺乳动物的致命神经退行性疾病，目前尚无治疗方法。在此，我们描述了一种新型抗朊病毒化合物依拉卡地（GW120918）的特性，它在朊病毒感染、传播和毒性检测中具有亚微摩尔活性。依拉卡地在朊病毒感染过程的早期起作用，增强新形成的朊蛋白的降解。基于转录组分析和功能性溶酶体探针的使用，溶酶体可能是依拉卡地抗朊病毒作用的位点。依拉卡地改变了控制溶酶体固醇和脂质代谢的基因表达网络，但与其他溶酶体促渗药物不同的是，它显著上调控制溶酶体pH值的基因。令人惊讶的是，这些作用独立于转录因子EB（TFEB）的核转位，提示了新的调控机制。依拉卡地的抗朊病毒作用扩展到α-突触核蛋白和tau朊病毒，突出了溶酶体增强作为治疗蛋白质错误折叠神经退行性疾病的一种通用策略。
