Enhanced Preprints

Cardiac glycosides restore autophagy flux in an iPSC-derived neuronal model of WDR45 deficiency

  1. Apostolos Papandreou
  2. Nivedita Singh
  3. Lorita Gianfrancesco
  4. Dimitri Budinger
  5. Katy Barwick
  6. Alexander Agrotis
  7. Christin Luft
  8. Ying Shao
  9. An-Sofie Lenaerts
  10. Allison Gregory
  11. Suh Young Jeong
  12. Penelope Hogarth
  13. Susan Hayflick
  14. Serena Barral
  15. Janos Kriston-Vizi
  16. Paul Gissen
  17. Manju A Kurian author has email address
  18. Robin Ketteler author has email address
  1. Developmental Neurosciences, Zayed Centre for Research into Rare Disease in Children, University College London Great Ormond Street Institute of Child Health, London, UK
  2. Laboratory for Molecular Cell Biology, University College London, London, UK
  3. Department of Neurology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
  4. Wellcome-MRC Cambridge Stem Cell Institute, Cambridge, UK
  5. Oregon Health and Science University, Portland, OR, USA
  6. Inborn Errors of Metabolism, Genetics & Genomic Medicine Programme, Great Ormond Street Institute of Child Health, University College London, London, UK
  7. Department of Metabolic Medicine, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
  8. Department of Human Medicine, Medical School Berlin, Berlin, Germany

Peer review process

Not revised: This Reviewed Preprint includes the authors’ original preprint (without revision), an eLife assessment, public reviews, and a response from the authors (if available).

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Editors

  • Reviewing Editor
    Ivan Velasco
    Universidad Nacional Autónoma de México, Mexico City, Mexico
  • Senior Editor
    Ma-Li Wong
    State University of New York Upstate Medical University, Syracuse, United States of America

Reviewer #1 (Public Review):

Summary:
In the current study, Papandreou et al. developed an iPSC-based midbrain dopaminergic neuronal cell model of Beta-Propeller Protein-Associated Neurodegeneration (BPAN), which is caused by mutations in the WDR45 gene and is known to impair autophagy. They also noted defective autophagy and abnormal BPAN-related gene expression signatures. Further, they performed a drug screening and identified five cardiac glycosides. Treatment with these drugs effectively in improved autophagy defects and restored gene expression.

Strengths:
Seeing the autophagy defects and impaired expression of BPAN-related genes adds strength to this study. Importantly, this work shows the value of iPSC-based modeling in studying disease and finding therapeutic strategies for genetic disorders, including BPAN.

Weaknesses:
It is unclear whether these cells show iron metabolism defects and whether treatment with these drugs can ameliorate the iron metabolism phenotypes.

Reviewer #2 (Public Review):

Summary:
In this manuscript, the authors aim to demonstrate that cardiac glycosides restore autophagy flux in an iPSC-derived mDA neuronal model of WDR45 deficiency. They established a patient-derived induced pluripotent stem cell (iPSC)-based midbrain dopaminergic (mDA) neuronal model and performed a medium-throughput drug screen using high-content imaging-based IF analysis. Several compounds were identified to ameliorate disease-specific phenotypes in vitro.

Strengths:
This manuscript engaged in an important topic and yielded some interesting data.

Weaknesses:
This manuscript failed to provide solid evidence to support the conclusion.

  1. Howard Hughes Medical Institute
  2. Wellcome Trust
  3. Max-Planck-Gesellschaft
  4. Knut and Alice Wallenberg Foundation