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LYST deficiency impairs autophagic lysosome reformation in neurons and alters lysosome number and size

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A Correction to this article was published on 04 March 2023

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Abstract

Chediak–Higashi syndrome (CHS) is a rare, autosomal recessive disorder caused by biallelic mutations in the lysosomal trafficking regulator (LYST) gene. Even though enlarged lysosomes and/or lysosome-related organelles (LROs) are the typical cellular hallmarks of CHS, they have not been investigated in human neuronal models. Moreover, how and why the loss of LYST function causes a lysosome phenotype in cells has not been elucidated. We report that the LYST-deficient human neuronal model exhibits lysosome depletion accompanied by hyperelongated tubules extruding from enlarged autolysosomes. These results have also been recapitulated in neurons differentiated from CHS patients’ induced pluripotent stem cells (iPSCs), validating our model system. We propose that LYST ensures the correct fission/scission of the autolysosome tubules during autophagic lysosome reformation (ALR), a crucial process to restore the number of free lysosomes after autophagy. We further demonstrate that LYST is recruited to the lysosome membrane, likely to facilitate the fission of autolysosome tubules. Together, our results highlight the key role of LYST in maintaining lysosomal homeostasis following autophagy and suggest that ALR dysregulation is likely associated with the neurodegenerative CHS phenotype.

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Acknowledgements

The authors acknowledge National Human Genome Research Institute cytogenetics core for the iPSCs karyotyping; Stewart W. Humble (National Institute of Neurological Disorders and Stroke), Michael S. Fernandopulle (National Institute of Neurological Disorders and Stroke) and Jorge Gomez-Deza (Eunice Kennedy Shriver National Institute of Child Health and Human Development) for the technical advice. The authors also thank the Microfabrication and Microfluidics Unit of the Biomedical Engineering and Physical Science Shared Resource, National Institute of Biomedical Imaging and Bioengineering, for the assistance in the fabrication of the PDMS microdevices and templates; and Clàudia Serra Vinardell for her assistance in preparing graphic illustrations.

Funding

This study is supported by the Intramural Research Programs of the National Human Genome Research Institute, National Institute of Child Health and Human Development, National Institute of Allergy and Infectious Diseases and National Heart, Lung, and Blood Institute of the National Institutes of Health.

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Authors and Affiliations

  1. Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA

    Jenny Serra-Vinardell, Maxwell B. Sandler, Wendy J. Introne, William A. Gahl & May Christine V. Malicdan

  2. Neurosciences and Cellular and Structural Biology Division, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA

    Raffaella De Pace

  3. Twinbrook Imaging Facility, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, 20892, USA

    Javier Manzella-Lapeira & Joseph A. Brzostowski

  4. Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA

    Antony Cougnoux

  5. National Heart, Lung, and Blood Institute, Flow Cytometry Facility, National Institutes of Health, Bethesda, MD, 20892, USA

    Keyvan Keyvanfar

  6. National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, 20892, USA

    Michael E. Ward

  7. Undiagnosed Diseases Program, National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Common Fund, Office of the Director, NIH, Bethesda, MD, 20892, USA

    William A. Gahl, Prashant Sharma & May Christine V. Malicdan

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  1. Jenny Serra-Vinardell
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Contributions

JS-V, MBS, PS designing and conducting experiments, data analysis and interpretation, manuscript preparation-first draft, review, and editing. RDP helped with the trafficking experiments and data analysis. JM-L, JAB and AC contributed on microscopy data analysis. KK performed the bulk and single-cell sorting. WJI provided the CHS patients resources. MEW provided the i3N iPSC line and plasmids. WAG funding acquisition, review, and editing. MCCM review and editing.

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Correspondence to Jenny Serra-Vinardell or Prashant Sharma.

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Serra-Vinardell, J., Sandler, M.B., De Pace, R. et al. LYST deficiency impairs autophagic lysosome reformation in neurons and alters lysosome number and size. Cell. Mol. Life Sci. 80, 53 (2023). https://doi.org/10.1007/s00018-023-04695-x

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