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Adipose deficiency and aberrant autophagy in a Drosophila model of MPS VII is corrected by pharmacological stimulators of mTOR.
- Source :
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BBA: Molecular Basis of Disease . Jul2022, Vol. 1868 Issue 7, pN.PAG-N.PAG. 1p. - Publication Year :
- 2022
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Abstract
- Mucopolysaccharidosis type VII (MPS VII) is a recessively inherited lysosomal storage disorder caused due to β-glucuronidase (β-GUS) enzyme deficiency. Prominent clinical symptoms include hydrops fetalis, musculoskeletal deformities, neurodegeneration and hepatosplenomegaly leading to premature death in most cases. Apart from these, MPS VII is also characterized as adipose storage deficiency disorder although the underlying mechanism of this lean phenotype in the patients or β-GUS-deficient mice still remains a mystery. We addressed this issue using our recently developed Drosophila model of MPS VII (the CG2135-/- fly), which also exhibited a significant loss of body fat. We report here that the lean phenotype of the CG2135−/− larvae is due to fewer number of adipocytes, smaller lipid droplets and reduced adipogenesis. Our data further revealed that there is an abnormal accumulation of autophagosomes in the CG2135−/− larvae due to autophagosome-lysosome fusion defect. Decreased lysosome-mediated turnover also led to attenuated mTOR activity in the CG2135−/− larvae. Interestingly, treatment of the CG2135−/− larvae with mTOR stimulators, 3BDO or glucose, led to the restoration of mTOR activity with simultaneous correction of the autophagy defect and adipose storage deficiency. Our finding thus established a hitherto unknown mechanistic link between autophagy dysfunction, mTOR downregulation and reduced adiposity in MPS VII. [Display omitted] • β-Glucuronidase (CG2135) loss of function in Drosophila perturbs adipogenesis and leads to a lean phenotype. • Impaired autophagosome-lysosome fusion in the CG2135−/− larval fat tissue results in aberrant accumulation of autophagosomes. • Stimulation of mTOR in the CG2135−/− larvae with glucose and 3-BDO rescued defective autophagy and adipose deficiency. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 09254439
- Volume :
- 1868
- Issue :
- 7
- Database :
- Academic Search Index
- Journal :
- BBA: Molecular Basis of Disease
- Publication Type :
- Academic Journal
- Accession number :
- 156319419
- Full Text :
- https://doi.org/10.1016/j.bbadis.2022.166399