Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, NY 10962, USA; Department of Psychiatry, New York University Langone Medical Center, New York, NY 10016, USA.
Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, NY 10962, USA.
Cell Rep. 2021 Apr 27;35(4):109034. doi: 10.1016/j.celrep.2021.109034.
Lysosomal trafficking and maturation in neurons remain poorly understood and are unstudied in vivo despite high disease relevance. We generated neuron-specific transgenic mice to track vesicular CTSD acquisition, acidification, and traffic within the autophagic-lysosomal pathway in vivo, revealing that mature lysosomes are restricted from axons. Moreover, TGN-derived transport carriers (TCs), not lysosomes, supply lysosomal components to axonal organelles. Ultrastructurally distinctive TCs containing TGN and lysosomal markers enter axons, engaging autophagic vacuoles and late endosomes. This process is markedly upregulated in dystrophic axons of Alzheimer models. In cultured neurons, most axonal LAMP1 vesicles are weakly acidic TCs that shuttle lysosomal components bidirectionally, conferring limited degradative capability to retrograde organelles before they mature fully to lysosomes within perikarya. The minor LAMP1 subpopulation attaining robust acidification are retrograde Rab7 endosomes/amphisomes, not lysosomes. Restricted lysosome entry into axons explains the unique lysosome distribution in neurons and their vulnerability toward neuritic dystrophy in disease.
神经元中的溶酶体运输和成熟仍然知之甚少，尽管与疾病高度相关，但在体内尚未得到研究。我们生成了神经元特异性转基因小鼠，以追踪囊泡 CTSD 在体内的自噬溶酶体途径中的获得、酸化和运输，结果表明成熟的溶酶体被限制在轴突之外。此外，TGN 衍生的运输载体（TCs）而不是溶酶体为轴突细胞器提供溶酶体成分。含有 TGN 和溶酶体标记物的超微结构独特的 TCs 进入轴突，与自噬空泡和晚期内体结合。该过程在阿尔茨海默病模型的病变轴突中明显上调。在培养的神经元中，大多数轴突 LAMP1 囊泡是弱酸性的 TCs，它们双向运输溶酶体成分，在逆行细胞器完全成熟为胞质溶酶体之前，赋予其有限的降解能力。少数能够实现强酸化的 LAMP1 亚群是逆行 Rab7 内体/吞噬体，而不是溶酶体。溶酶体进入轴突的受限解释了神经元中独特的溶酶体分布及其在疾病中对神经突营养不良的脆弱性。
