VMA21 deficiency prevents vacuolar ATPase assembly and causes autophagic vacuolar myopathy.
Acta Neuropathol
; 125(3): 439-57, 2013 Mar.
Article
en En
| MEDLINE
| ID: mdl-23315026
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.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Autofagia
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Enfermedades por Almacenamiento Lisosomal
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Adenosina Trifosfatasas
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ATPasas de Translocación de Protón Vacuolares
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Enfermedades Musculares
Tipo de estudio:
Etiology_studies
Límite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Acta Neuropathol
Año:
2013
Tipo del documento:
Article
País de afiliación:
Canadá