Molecular basis for dyneinopathies reveals insight into dynein regulation and dysfunction

  1. Matthew G Marzo
  2. Jacqueline M Griswold
  3. Kristina M Ruff
  4. Rachel E Buchmeier
  5. Colby P Fees
  6. Steven M Markus  Is a corresponding author
  1. Colorado State University, United States
  2. University of Colorado School of Medicine, United States

Abstract

Cytoplasmic dynein plays critical roles within the developing and mature nervous systems, including effecting nuclear migration, and retrograde transport of various cargos. Unsurprisingly, mutations in dynein are causative of various developmental neuropathies and motor neuron diseases. These 'dyneinopathies' define a broad spectrum of diseases with no known correlation between mutation identity and disease state. To circumvent complications associated with dynein studies in human cells, we employed budding yeast as a screening platform to characterize the motility properties of seventeen disease-correlated dynein mutants. Using this system, we determined the molecular basis for several classes of etiologically related diseases. Moreover, by engineering compensatory mutations, we alleviated the mutant phenotypes in two of these cases, one of which we confirmed with recombinant human dynein. In addition to revealing molecular insight into dynein regulation, our data provide additional evidence that the type of disease may in fact be dictated by the degree of dynein dysfunction.

Data availability

All of the data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for all figures.

Article and author information

Author details

  1. Matthew G Marzo

    Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Jacqueline M Griswold

    Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Kristina M Ruff

    Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Rachel E Buchmeier

    Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Colby P Fees

    Department of Cell and Developmental Biology, University of Colorado School of Medicine, Aurora, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Steven M Markus

    Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, United States
    For correspondence
    steven.markus@colostate.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3098-0236

Funding

Muscular Dystrophy Association (376387)

  • Matthew G Marzo
  • Jacqueline M Griswold
  • Kristina M Ruff
  • Rachel E Buchmeier
  • Steven M Markus

National Institute of General Medical Sciences (GM 118492)

  • Matthew G Marzo
  • Steven M Markus

National Institute of General Medical Sciences (GM 112893)

  • Colby P Fees

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

Reviewing Editor

  1. Andrew P Carter, MRC Laboratory of Molecular Biology, United Kingdom

Version history

  1. Received: March 29, 2019
  2. Accepted: July 30, 2019
  3. Accepted Manuscript published: July 31, 2019 (version 1)
  4. Version of Record published: September 9, 2019 (version 2)

Copyright

© 2019, Marzo 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. Matthew G Marzo
  2. Jacqueline M Griswold
  3. Kristina M Ruff
  4. Rachel E Buchmeier
  5. Colby P Fees
  6. Steven M Markus
(2019)
Molecular basis for dyneinopathies reveals insight into dynein regulation and dysfunction
eLife 8:e47246.
https://doi.org/10.7554/eLife.47246

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https://doi.org/10.7554/eLife.47246

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