ABSTRACT

Efficient degradation of autophagic vacuoles (AVs) generated at axon terminals by mature lysosomes enriched in the cell body represents an exceptional challenge that neurons face in maintaining cellular homeostasis. Here, we discuss our recent findings revealing a lipid-mediated impairment of lysosome transport to distal axons contributing to axonal AV accumulation in the neurodegenerative lysosomal storage disorder Niemann-Pick disease type C (NPC). Using transmission electron microscopy, we observed a striking buildup of endocytic and autophagic organelles in NPC dystrophic axons, indicating defects in the clearance of organelles destined for lysosomal degradation. We further revealed that elevated cholesterol on NPC lysosome membranes abnormally sequesters motor-adaptors of axonal lysosome delivery, resulting in impaired anterograde lysosome transport into distal axons that disrupts maturation of axonal AVs during their retrograde transport route. Together, our study demonstrates a mechanism by which altered membrane lipid composition compromises axonal lysosome trafficking and positioning and shows that lowering lysosomal lipid levels rescues lysosome transport into NPC axons, thus reducing axonal autophagic stress at early stages of NPC disease.

摘要

细胞体中富集的成熟溶酶体有效降解轴突末端产生的自噬泡 (AVs) 代表了神经元在维持细胞稳态方面面临的特殊挑战。在这里，我们讨论了我们最近的研究结果，这些发现揭示了脂质介导的溶酶体转运到远端轴突的损伤，导致神经退行性溶酶体贮积症 Niemann-Pick 病 C 型 (NPC) 轴突 AV 积累。使用透射电子显微镜，我们观察到 NPC 营养不良轴突中内吞和自噬细胞器的显着积累，表明用于溶酶体降解的细胞器的清除存在缺陷。我们进一步揭示了 NPC 溶酶体膜上升高的胆固醇异常隔离了轴突溶酶体传递的运动适配器，导致向远端轴突的顺行溶酶体转运受损，从而在其逆行转运路线中破坏轴突 AV 的成熟。总之，我们的研究证明了一种机制，通过该机制改变的膜脂质成分会损害轴突溶酶体的运输和定位，并表明降低溶酶体脂质水平可以挽救溶酶体转运到 NPC 轴突，从而减少 NPC 疾病早期阶段的轴突自噬应激。