A1 Refereed original research article in a scientific journal
VMA21 deficiency prevents vacuolar ATPase assembly and causes autophagic vacuolar myopathy
Authors: Ramachandran N, Munteanu I, Wang P, Ruggieri A, Rilstone JJ, Israelian N, Naranian T, Paroutis P, Guo R, Ren Z, Nishino I, Chabrol B, Pellissier J, Minetti C, Udd B, Fardeau M, Tailor CS, Mahuran DJ, Kissel JT, Kalimo H, Levy N, Manolson MF, Ackerley CA, Minassian BA
Publisher: SPRINGER
Publishing place: NEW YORK; 233 SPRING ST, NEW YORK, NY 10013 USA
Publication year: 2013
Journal: Acta Neuropathologica
Journal name in source: Acta Neuropathologica
Journal acronym: Acta Neuropathol.
Number in series: 3
Volume: 125
Issue: 3
First page : 439
Last page: 457
Number of pages: 19
ISSN: 0001-6322
DOI: https://doi.org/10.1007/s00401-012-1073-6
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.
