Ca²⁺ is the most ubiquitous second messenger in neurons whose spatial and temporal elevations are tightly controlled to initiate and orchestrate diverse intracellular signaling cascades. Numerous neuropathologies result from mutations or alterations in Ca²⁺ handling proteins; thus, elucidating molecular pathways that shape Ca²⁺ signaling is imperative. Here, we report that loss-of-function, knockout, or neurodegenerative disease–causing mutations in the lysosomal cholesterol transporter, Niemann-Pick Type C1 (NPC1), initiate a damaging signaling cascade that alters the expression and nanoscale distribution of IP₃R type 1 (IP₃R1) in endoplasmic reticulum membranes. These alterations detrimentally increase G_q-protein coupled receptor–stimulated Ca²⁺ release and spontaneous IP₃R1 Ca²⁺ activity, leading to mitochondrial Ca²⁺ cytotoxicity. Mechanistically, we find that SREBP-dependent increases in Presenilin 1 (PS1) underlie functional and expressional changes in IP₃R1. Accordingly, expression of PS1 mutants recapitulate, while PS1 knockout abrogates Ca²⁺ phenotypes. These data present a signaling axis that links the NPC1 lysosomal cholesterol transporter to the damaging redistribution and activity of IP₃R1 that precipitates cell death in NPC1 disease and suggests that NPC1 is a nanostructural disease.

Ca ²⁺是神经元中最普遍的第二信使，其空间和时间高度受到严格控制，以启动和协调不同的细胞内信号级联。许多神经病理学是由 Ca ²⁺处理蛋白的突变或改变引起的；因此，阐明形成 Ca ²⁺信号传导的分子途径势在必行。在此，我们报告称，溶酶体胆固醇转运蛋白 Niemann-Pick C1 型 (NPC1) 的功能丧失、敲除或神经退行性疾病引起的突变会启动破坏性信号级联反应，从而改变 IP 3 R 的表达和纳米_级分布内质网膜中的1 型 (IP _{3 R1)。}这些改变有害地增加了 G _q蛋白偶联受体刺激的 Ca ²⁺释放和自发 IP ₃ R1 Ca ²⁺活性，导致线粒体 Ca ²⁺细胞毒性。从机制上讲，我们发现早老素 1 (PS1) 的 SREBP 依赖性增加是 IP ₃ R1 功能和表达变化的基础。因此，PS1 突变体的表达重现，而 PS1 敲除消除了 Ca ²⁺表型。_{这些数据提出了一个信号轴，将 NPC1 溶酶体胆固醇转运蛋白与 IP 3} R1的破坏性重新分布和活性联系起来，从而导致 NPC1 疾病中的细胞死亡，并表明 NPC1 是一种纳米结构疾病。