Synaptic Function Section, The Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
Department of Pharmacology, University of Oxford, Oxford, UK.
Autophagy. 2021 Jul;17(7):1796-1798. doi: 10.1080/15548627.2021.1938916. Epub 2021 Jun 30.
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.
通过富含成熟溶酶体的细胞体高效降解轴突末端产生的自噬小体（AVs），代表了神经元在维持细胞内稳态方面面临的一个特殊挑战。在这里，我们讨论了我们最近的发现，揭示了脂质介导的溶酶体向远端轴突运输的损伤，导致神经退行性溶酶体贮积症尼曼-匹克病 C 型（NPC）中轴突 AV 积累。通过透射电子显微镜观察，我们观察到 NPC 营养不良轴突中内吞和自噬细胞器的大量堆积，表明用于溶酶体降解的细胞器清除存在缺陷。我们进一步揭示 NPC 溶酶体膜上升高的胆固醇异常隔离了轴突溶酶体递送的运动衔接物，导致顺行溶酶体向远端轴突的运输受损，破坏了 AVs 在逆行运输过程中的成熟。总之，我们的研究表明，改变膜脂质组成会损害轴突溶酶体运输和定位的机制，并表明降低溶酶体脂质水平可挽救 NPC 轴突中的溶酶体运输，从而减少 NPC 疾病早期的轴突自噬应激。
