Brain-matter vacuolation is a defining trait of all prion diseases, yet its cause is unknown. Here, we report that prion infection and prion-mimetic antibodies deplete the phosphoinositide kinase PIKfyve—which controls endolysosomal maturation—from mouse brains, cultured cells, organotypic brain slices, and brains of Creutzfeldt-Jakob disease victims. We found that PIKfyve is acylated by the acyltransferases zDHHC9 and zDHHC21, whose juxtavesicular topology is disturbed by prion infection, resulting in PIKfyve deacylation and rapid degradation, as well as endolysosomal hypertrophy and activation of TFEB-dependent lysosomal enzymes. A protracted unfolded protein response (UPR), typical of prion diseases, also induced PIKfyve deacylation and degradation. Conversely, UPR antagonists restored PIKfyve levels in prion-infected cells. Overexpression of zDHHC9 and zDHHC21, administration of the antiprion polythiophene LIN5044, or supplementation with the PIKfyve reaction product PI(3,5)P₂ suppressed prion-induced vacuolation and restored lysosomal homeostasis. Thus, PIKfyve emerges as a central mediator of vacuolation and neurotoxicity in prion diseases.

中文翻译：

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PIKfyve 的缺失驱动了朊病毒疾病的海绵状变性

脑物质空泡化是所有朊病毒疾病的一个决定性特征，但其原因尚不清楚。在这里，我们报告朊病毒感染和朊病毒模拟抗体消耗了来自小鼠大脑、培养细胞、器官型脑切片和克雅氏病患者大脑的磷酸肌醇激酶 PIKfyve（控制内溶酶体成熟）。我们发现 PIKfyve 被酰基转移酶 zDHHC9 和 zDHHC21 酰化，其近泡拓扑结构受到朊病毒感染的干扰，导致 PIKfyve 脱酰和快速降解，以及内溶酶体肥大和 TFEB 依赖性溶酶体酶的激活。一种典型的朊病毒疾病的长期未折叠蛋白反应 (UPR) 也诱导 PIKfyve 脱酰和降解。相反，UPR 拮抗剂恢复了朊病毒感染细胞中的 PIKfyve 水平。₂抑制朊病毒诱导的空泡形成并恢复溶酶体稳态。因此，PIKfyve 成为朊病毒疾病中空泡形成和神经毒性的中心介质。