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VMA21 deficiency prevents vacuolar ATPase assembly and causes autophagic vacuolar myopathy |
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| Authors: | Nivetha Ramachandran Iulia Munteanu Peixiang Wang Alessandra Ruggieri Jennifer J. Rilstone Nyrie Israelian Taline Naranian Paul Paroutis Ray Guo Zhi-Ping Ren Ichizo Nishino Brigitte Chabrol Jean-Francois Pellissier Carlo Minetti Bjarne Udd Michel Fardeau Chetankumar S. Tailor Don J. Mahuran John T. Kissel Hannu Kalimo Nicolas Levy Morris F. Manolson Cameron A. Ackerley Berge A. Minassian |
| Affiliation: | 1. Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada 2. Institute of Medical Sciences, University of Toronto, Toronto, ON, M5S 1A8, Canada 3. Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London, WC1N 1EH, UK 4. Program in Cell Biology, The Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada 5. Department of Neuromuscular Research, National Center of Neurology and Psychiatry, Kodaira, Tokyo, 187-8502, Japan 6. Unité de Médecine Infantile, H?pital D’enfants, CHU de la Timone, 13385, Marseille, France 7. Laboratoire d’Anatomie Pathologique et Neuropathologie, H?pital de la Timone, 13385, Marseille, France 8. Muscular and Neurodegenerative Disease Unit, G. Gaslini Institute and University of Genova, 16147, Genoa, Italy 9. Department of Neurology, Vaasa Central Hospital and Tampere University, FI-65130, Vaasa, Finland 10. Myology Institute, Salpetriere Hospital, 75013, Paris, France 11. Department of Neurology, Ohio State University, Columbus, OH, 43210, USA 12. Haartman Institute Department of Pathology, University of Helsinki, FI-00014, Helsingin, Yliopisto, Finland 13. Departments of Pathology and Forensic Medicine, Institute of Biomedicine, University of Turku, FI-20520, Turku, Finland 14. Faculté de Médecine de Marseille, Inserm UMR_S910, Université de la Méditerranée, 13385, Marseille, France 15. Faculty of Dentistry, University of Toronto, Toronto, ON, M5G 1G6, Canada 16. Department of Pathology and Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada 17. Division of Neurology, Department of Paediatrics, The Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada |
| Abstract: | X-linked Myopathy with Excessive Autophagy (XMEA) is a childhood onset disease characterized by progressive vacuolation and atrophy of skeletal muscle. We show that XMEA is caused by hypomorphic alleles of the VMA21 gene, that VMA21 is the diverged human ortholog of the yeast Vma21p protein, and that like Vma21p, VMA21 is an essential assembly chaperone of the vacuolar ATPase (V-ATPase), the principal mammalian proton pump complex. Decreased VMA21 raises lysosomal pH which reduces lysosomal degradative ability and blocks autophagy. This reduces cellular free amino acids which leads to downregulation of the mTORC1 pathway, and consequent increased macroautophagy resulting in proliferation of large and ineffective autolysosomes that engulf sections of cytoplasm, merge, and vacuolate the cell. Our results uncover a novel mechanism of disease, namely macroautophagic overcompensation leading to cell vacuolation and tissue atrophy. |
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