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VMA21 deficiency prevents vacuolar ATPase assembly and causes autophagic vacuolar myopathy.
- Source :
-
Acta neuropathologica [Acta Neuropathol] 2013 Mar; Vol. 125 (3), pp. 439-57. Date of Electronic Publication: 2013 Jan 12. - Publication Year :
- 2013
-
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.
- Subjects :
- Animals
Cells, Cultured
Humans
Hydrogen-Ion Concentration
Leucine metabolism
Lysosomal Storage Diseases pathology
Lysosomes genetics
Lysosomes metabolism
Male
Mice
Muscle, Skeletal metabolism
Muscle, Skeletal pathology
Muscle, Skeletal ultrastructure
Muscular Diseases pathology
Mutation genetics
RNA Interference physiology
RNA, Messenger genetics
Saccharomyces cerevisiae genetics
Saccharomyces cerevisiae metabolism
Saccharomyces cerevisiae Proteins genetics
Saccharomyces cerevisiae Proteins metabolism
Subcellular Fractions metabolism
Subcellular Fractions pathology
Time Factors
Vacuoles metabolism
Adenosine Triphosphatases metabolism
Autophagy genetics
Lysosomal Storage Diseases genetics
Lysosomal Storage Diseases prevention & control
Muscular Diseases genetics
Muscular Diseases prevention & control
Vacuolar Proton-Translocating ATPases deficiency
Vacuolar Proton-Translocating ATPases genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1432-0533
- Volume :
- 125
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Acta neuropathologica
- Publication Type :
- Academic Journal
- Accession number :
- 23315026
- Full Text :
- https://doi.org/10.1007/s00401-012-1073-6