Quantitative transportomics identifies Kif5a as a major regulator of neurodegeneration

  1. Sahil H Shah  Is a corresponding author
  2. Lucio M Schiapparelli
  3. Yuanhui Ma
  4. Satoshi Yokota
  5. Melissa Atkins
  6. Xin Xia
  7. Evan G Cameron
  8. Thanh Huang
  9. Sarah Saturday
  10. Catalin B Sun
  11. Cara Knasel
  12. Seth Blackshaw
  13. John R Yates III III
  14. Hollis T Cline
  15. Jeffrey L Goldberg
  1. Stanford University, United States
  2. The Scripps Research Institute, United States
  3. Johns Hopkins University School of Medicine, United States

Abstract

Many neurons in the adult central nervous system, including retinal ganglion cells (RGCs), degenerate and die after injury. Early axon protein and organelle trafficking failure is a key component in many neurodegenerative disorders yet changes to axoplasmic transport in disease models have not been quantified. We analyzed early changes in the protein 'transportome' from (RGC somas to their axons after optic nerve injury and identified transport failure of an anterograde motor protein Kif5a early in RGC degeneration. We demonstrated that manipulating Kif5a expression affects anterograde mitochondrial trafficking in RGCs and characterized axon transport in Kif5a knockout mice to identify proteins whose axon localization was Kif5a-dependent. Finally, we found that knockout of Kif5a in RGCs resulted in progressive RGC degeneration in the absence of injury. Together with expression data localizing Kif5a to human RGCs, these data identify Kif5a transport failure as a cause of RGC neurodegeneration and point to a mechanism for future therapeutics.

Data availability

All data generated during this study are included in the manuscript and supporting source files in excel format. Source data files have been provided for Figures 1, 4, 5 and Supplementary Figure 2.

The following previously published data sets were used

Article and author information

Author details

  1. Sahil H Shah

    Byers Eye Institute and Spencer Center for Vision Research, Stanford University, Palo Alto, United States
    For correspondence
    sahilshah90@gmail.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6601-219X
  2. Lucio M Schiapparelli

    Neuroscience Department, The Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Yuanhui Ma

    Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Satoshi Yokota

    Byers Eye Institute and Spencer Center for Vision Research, Stanford University, Palo Alto, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3727-7279
  5. Melissa Atkins

    Byers Eye Institute and Spencer Center for Vision Research, Stanford University, Palo Alto, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Xin Xia

    Byers Eye Institute and Spencer Center for Vision Research, Stanford University, Palo Alto, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Evan G Cameron

    Byers Eye Institute and Spencer Center for Vision Research, Stanford University, Palo Alto, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Thanh Huang

    Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Sarah Saturday

    Neuroscience Department, The Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Catalin B Sun

    Byers Eye Institute and Spencer Center for Vision Research, Stanford University, Palo Alto, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Cara Knasel

    Byers Eye Institute and Spencer Center for Vision Research, Stanford University, Palo Alto, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Seth Blackshaw

    Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1338-8476
  13. John R Yates III III

    Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5267-1672
  14. Hollis T Cline

    Neuroscience Department, The Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4887-9603
  15. Jeffrey L Goldberg

    Byers Eye Institute and Spencer Center for Vision Research, Stanford University, Palo Alto, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1390-7360

Funding

National Institutes of Health (EY011261)

  • Hollis T Cline

Research to Prevent Blindness

  • Jeffrey L Goldberg

National Institutes of Health (U01EY027261)

  • John R Yates III III
  • Hollis T Cline
  • Jeffrey L Goldberg

National Institutes of Health (EY027437)

  • Hollis T Cline

National Institutes of Health (P30 EY019005)

  • Hollis T Cline

National Institutes of Health (R01MH103134)

  • Hollis T Cline

National Institutes of Health (P41 GM103533)

  • John R Yates III III

Hahn Family Foundation

  • Hollis T Cline

National Institutes of Health (R01MH067880)

  • John R Yates III III

National Institutes of Health (P30 EY026877)

  • Jeffrey L Goldberg

Glaucoma Research Foundation

  • Jeffrey L Goldberg

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Paola Bovolenta, CSIC-UAM, Spain

Ethics

Animal experimentation: All animal experiments conformed to the ARVO statement for the Use of Animals in Ophthalmic and Vision Research and were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) and the Institutional Biosafety Committee of University of California, San Diego, Scripps Research, and Stanford University.

Version history

  1. Received: March 5, 2021
  2. Accepted: March 7, 2022
  3. Accepted Manuscript published: March 8, 2022 (version 1)
  4. Version of Record published: March 24, 2022 (version 2)

Copyright

© 2022, Shah 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. Sahil H Shah
  2. Lucio M Schiapparelli
  3. Yuanhui Ma
  4. Satoshi Yokota
  5. Melissa Atkins
  6. Xin Xia
  7. Evan G Cameron
  8. Thanh Huang
  9. Sarah Saturday
  10. Catalin B Sun
  11. Cara Knasel
  12. Seth Blackshaw
  13. John R Yates III III
  14. Hollis T Cline
  15. Jeffrey L Goldberg
(2022)
Quantitative transportomics identifies Kif5a as a major regulator of neurodegeneration
eLife 11:e68148.
https://doi.org/10.7554/eLife.68148

Share this article

https://doi.org/10.7554/eLife.68148

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