Post-Golgi carriers, not lysosomes, confer lysosomal properties to pre-degradative organelles in normal and dystrophic axons

• Published in: Cell reports (Cambridge) Vol. 35; no. 4; p. 109034
• Main Authors: Lie, Pearl P.Y., Yang, Dun-Sheng, Stavrides, Philip, Goulbourne, Chris N., Zheng, Ping, Mohan, Panaiyur S., Cataldo, Anne M., Nixon, Ralph A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27.04.2021
• Subjects: acidification; Animals; autophagic vacuole; axonal transport; Axons - metabolism; Disease Models, Animal; Golgi Apparatus - metabolism; LAMP1; late endosome; lysosome; Mice; Mice, Transgenic; Organelles - metabolism; post-Golgi traffic; transport carrier; transport carrier; autophagic vacuole; LAMP1; axonal transport; late endosome; acidification; lysosome; post-Golgi traffic
• ISSN: 2211-1247; 2211-1247
• 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. [Display omitted] •Fully mature classic lysosomes are restricted from axons in intact brains•Transport carriers (TCs) deliver lysosomal components from TGN to axonal organelles•TC delivery of lysosomal components is upregulated in dystrophic axons of AD models•Non-degradative bidirectional TCs in axons are commonly misidentified as lysosomes Lie et al. generate mouse models to demonstrate that, in vivo, fully mature lysosomes are restricted from axons. Instead, TGN-derived transport carriers supply lysosomal components to retrogradely transported pre-degradative vesicular compartments in axons for their maturation toward lysosomal identity, revealing insights into fundamental neurobiology of lysosomes in health and disease.