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LYST deficiency impairs autophagic lysosome reformation in neurons and alters lysosome number and size.
Serra-Vinardell, Jenny; Sandler, Maxwell B; De Pace, Raffaella; Manzella-Lapeira, Javier; Cougnoux, Antony; Keyvanfar, Keyvan; Introne, Wendy J; Brzostowski, Joseph A; Ward, Michael E; Gahl, William A; Sharma, Prashant; Malicdan, May Christine V.
Afiliación
  • Serra-Vinardell J; Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA. jennyserravinardell@gmail.com.
  • Sandler MB; Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
  • De Pace R; 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.
  • Manzella-Lapeira J; Twinbrook Imaging Facility, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, 20892, USA.
  • Cougnoux A; Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA.
  • Keyvanfar K; National Heart, Lung, and Blood Institute, Flow Cytometry Facility, National Institutes of Health, Bethesda, MD, 20892, USA.
  • Introne WJ; Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
  • Brzostowski JA; Twinbrook Imaging Facility, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, 20892, USA.
  • Ward ME; National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, 20892, USA.
  • Gahl WA; Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
  • Sharma P; 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.
  • Malicdan MCV; 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. sharmap@nih.gov.
Cell Mol Life Sci ; 80(2): 53, 2023 Jan 28.
Article en En | MEDLINE | ID: mdl-36707427
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Síndrome de Chediak-Higashi / Proteínas de Transporte Vesicular Límite: Humans Idioma: En Revista: Cell Mol Life Sci Asunto de la revista: BIOLOGIA MOLECULAR Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Suiza
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Síndrome de Chediak-Higashi / Proteínas de Transporte Vesicular Límite: Humans Idioma: En Revista: Cell Mol Life Sci Asunto de la revista: BIOLOGIA MOLECULAR Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Suiza