1. Cell Biology
  2. Neuroscience

VCP-dependent muscle degeneration is linked to defects in a dynamic tubular lysosomal network in vivo

  1. Alyssa E Johnson
  2. Huidy Shu
  3. Anna G Hauswirth
  4. Amy Tong
  5. Graeme W Davis  Is a corresponding author
  1. University of California, San Francisco, United States
https://doi.org/10.7554/eLife.07366
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  1. Alyssa E Johnson
  2. Huidy Shu
  3. Anna G Hauswirth
  4. Amy Tong
  5. Graeme W Davis
(2015)
VCP-dependent muscle degeneration is linked to defects in a dynamic tubular lysosomal network in vivo
eLife 4:e07366.
https://doi.org/10.7554/eLife.07366
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Abstract

Lysosomes are classically viewed as vesicular structures to which cargos are delivered for degradation. Here, we identify a network of dynamic, tubular lysosomes that extends throughout Drosophila muscle, in vivo. Live imaging reveals that autophagosomes merge with tubular lysosomes and that lysosomal membranes undergo extension, retraction, fusion and fission. The dynamics and integrity of this tubular lysosomal network requires VCP, an AAA-ATPase that, when mutated, causes degenerative diseases of muscle, bone and neurons. We show that human VCP rescues the defects caused by loss of Drosophila VCP and overexpression of disease relevant VCP transgenes dismantles tubular lysosomes, linking tubular lysosome dysfunction to human VCP-related diseases. Finally, disruption of tubular lysosomes correlates with impaired autophagosome-lysosome fusion, increased cytoplasmic poly-ubiquitin aggregates, lipofuscin material, damaged mitochondria and impaired muscle function. We propose that VCP sustains sarcoplasmic proteostasis, in part, by controlling the integrity of a dynamic tubular lysosomal network.

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Author details

  1. Alyssa E Johnson

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.

  2. Huidy Shu

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.

  3. Anna G Hauswirth

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.

  4. Amy Tong

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.

  5. Graeme W Davis

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    For correspondence
    graeme.davis@ucsf.edu
    Competing interests
    Graeme W Davis, Reviewing editor eLife.

Copyright

© 2015, Johnson et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Alyssa E Johnson
  2. Huidy Shu
  3. Anna G Hauswirth
  4. Amy Tong
  5. Graeme W Davis
(2015)
VCP-dependent muscle degeneration is linked to defects in a dynamic tubular lysosomal network in vivo
eLife 4:e07366.
https://doi.org/10.7554/eLife.07366

Share this article

https://doi.org/10.7554/eLife.07366

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