Synaptic Vesicle Precursors and Lysosomes Are Transported by Different Mechanisms in the Axon of Mammalian Neurons

Pace, Raffaella De; Britt, Dylan; Mercurio, Jeffrey; Foster, Arianne M.; Djavaherian, Lucas; Hoffmann, Victoria; Abebe, Daniel; Bonifacino, Juan S.

doi:10.1016/j.celrep.2020.107775

Cited by 51 publications

(47 citation statements)

References 88 publications

(146 reference statements)

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“…We also detected larger light-lumen vesicles. These had a diameter of 70 - 170 nm and may correspond to less well characterized axonal compartments such as synaptic vesicle precursors or early endosomes (Pace et al, 2020; Wang et al, 2016; Wu et al, 2017). Vesicles with a dark lumen had an average diameter of 95 nm with the majority ranging from 70 to 120 nm.…”

Section: Resultsmentioning

confidence: 99%

A cryo-ET survey of intracellular compartments within mammalian axons

Foster

2021

Preprint

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The neuronal axon contains many intracellular compartments which travel between the cell body and axon tip. The nature of these cargos and the complex axonal environment through which they traverse is unclear. Here, we describe the internal components of mammalian sensory axons using cryo-electron tomography. We show that axonal endoplasmic reticulum has thin, beaded appearance and is tethered to microtubules at multiple sites. The tethers are elongated, ~7 nm long proteins which cluster in small groups. We survey the different membrane-bound cargos in axons, quantify their abundance and describe novel internal features including granules and broken membranes. We observe connecting density between membranes and microtubules which may correspond to motor proteins. In addition to membrane-bound organelles, we detect numerous proteinaceous compartments, including vaults and previously undescribed virus-like capsid particles. The abundance of these compartments suggests they undergo trafficking in axons. Our observations outline the physical characteristics of axonal cargo and provide a platform for identification of their constituents.

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Section: Resultsmentioning

confidence: 99%

A cryo-ET survey of intracellular compartments within mammalian axons

Foster

2021

Preprint

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“…At steady state, lysosomes exhibit a characteristic distribution, consisting of a densely packed population in the juxtanuclear area and a scattered population in the periphery of the cell (reviewed by (Ballabio and Bonifacino, 2020;Bonifacino and Neefjes, 2017). In polarized cells such as neurons, the peripheral population of lysosomes includes distinct pools in specialized domains of the cells (e.g., axon and dendrites) (De Pace et al, 2020;Farfel-Becker et al, 2019;Farias et al, 2017;Lee et al, 2011;Tsuruta and Dolmetsch, 2015). The overall distribution of lysosomes results from the integration of various processes, including tethering to other organelles such as the endoplasmic reticulum (ER) (Jongsma et al, 2016;Raiborg et al, 2015;Rocha et al, 2009;Saric et al, 2021) and mobilization by coupling to microtubule motors (Harada et al, 1998;Hollenbeck and Swanson, 1990).…”

Section: Discussionmentioning

confidence: 99%

“…For both GTPases, there must be other regulators that determine the interaction with alternative adaptors and, consequently, the direction of lysosome transport. Nevertheless, the role of ARL8 in anterograde transport seems to be dominant over that in retrograde transport, since depletion of ARL8 or its positive regulator BORC cause juxtanuclear clustering of lysosomes, whereas overexpression of ARL8 drives lysosomes to the cell periphery (De Pace et al, 2020;Farias et al, 2017;Guardia et al, 2016;Keren-Kaplan and Bonifacino, 2021;Korolchuk et al, 2011;Pu et al, 2015;Rosa-Ferreira and Munro, 2011). Future studies will have to address under what conditions ARL8 promotes lysosome retrograde transport mediated by RUFY3 and RUFY4.…”

Section: Discussionmentioning

confidence: 99%

RUFY3 and RUFY4 are ARL8 effectors that couple lysosomes to dynein-dynactin

Keren-Kaplan¹,

Sarić²,

Ghosh³

et al. 2021

Preprint

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The small GTPase ARL8 associates with lysosomes and recruits several effectors that mediate coupling to kinesins for anterograde transport, as well as tethering for eventual fusion with other organelles. Herein we report the identification of the “RUN- and FYVE-domain-containing” proteins RUFY3 and RUFY4 as novel ARL8 effectors that couple lysosomes to dynein-dynactin for retrograde transport. Using various biochemical approaches, we find that RUFY3/4 interact with both GTP-bound ARL8 and dynein-dynactin. In addition, we show that RUFY3/4 are both necessary and sufficient for concentration of lysosomes in the juxtanuclear area of the cell. RUFY3/4 also promote retrograde transport of lysosomes in the axon of hippocampal neurons. The function of RUFY3/4 in retrograde transport is required for juxtanuclear redistribution of lysosomes upon serum starvation or cytoplasmic alkalinization, and may underlie the reported roles of RUFY3/4 in axon development/degeneration, cancer and immunity. These studies thus establish RUFY3/4 as novel ARL8-dependent, dynein-dynactin adaptors, and highlight the role of ARL8 in the regulation of both anterograde and retrograde lysosome transport.

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“…It covers rather long distances and is affected by lysosome size [ 62 ]. As for other types of vesicle transport, it requires the interaction among motor proteins, regulators, and adaptors [ 63 ], although specific components such as BORC (BLOC-one-related complex, where BLOC stands for biogenesis of lysosome-related organelles complex) are required for the transport of lysosomes, but not of synaptic vesicle precursors in mammalian axons [ 64 ].…”

Section: Lysosomal Exocytosismentioning

confidence: 99%

Lysosomal Exocytosis: The Extracellular Role of an Intracellular Organelle

et al. 2020

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Lysosomes are acidic cell compartments containing a large set of hydrolytic enzymes. These lysosomal hydrolases degrade proteins, lipids, polysaccharides, and nucleic acids into their constituents. Materials to be degraded can reach lysosomes either from inside the cell, by autophagy, or from outside the cell, by different forms of endocytosis. In addition to their degradative functions, lysosomes are also able to extracellularly release their contents by lysosomal exocytosis. These organelles move from the perinuclear region along microtubules towards the proximity of the plasma membrane, then the lysosomal and plasma membrane fuse together via a Ca2+-dependent process. The fusion of the lysosomal membrane with plasma membrane plays an important role in plasma membrane repair, while the secretion of lysosomal content is relevant for the remodelling of extracellular matrix and release of functional substrates. Lysosomal storage disorders (LSDs) and age-related neurodegenerative disorders, such as Parkinson’s and Alzheimer’s diseases, share as a pathological feature the accumulation of undigested material within organelles of the endolysosomal system. Recent studies suggest that lysosomal exocytosis stimulation may have beneficial effects on the accumulation of these unprocessed aggregates, leading to their extracellular elimination. However, many details of the molecular machinery required for lysosomal exocytosis are only beginning to be unravelled. Here, we are going to review the current literature on molecular mechanisms and biological functions underlying lysosomal exocytosis, to shed light on the potential of lysosomal exocytosis stimulation as a therapeutic approach.

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Synaptic Vesicle Precursors and Lysosomes Are Transported by Different Mechanisms in the Axon of Mammalian Neurons

Cited by 51 publications

References 88 publications

A cryo-ET survey of intracellular compartments within mammalian axons

A cryo-ET survey of intracellular compartments within mammalian axons

RUFY3 and RUFY4 are ARL8 effectors that couple lysosomes to dynein-dynactin

Lysosomal Exocytosis: The Extracellular Role of an Intracellular Organelle

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