Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038187 (starvation)
 24,951 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations in MCOLN1, which encodes the protein h-mucolipin-1, result in the lysosomal storage disease Mucolipidosis Type IV. Studies on CUP-5, the human orthologue of h-mucolipin-1 in Caenorhabditis elegans, have shown that these proteins are required for lysosome biogenesis. We show here that the lethality in cup-5 mutant worms is due to two defects, starvation of embryonic cells and general developmental defects. Starvation leads to apoptosis through a CED-3-mediated pathway. We also show that providing worms with a lipid-soluble metabolite partially rescues the embryonic lethality but has no effect on the developmental defects, the major cause of the lethality. These results indicate that supplementing the metabolic deficiency of Mucolipidosis Type IV patients mat not be sufficient to alleviate the symptoms due to tissue degeneration.
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PMID:Basis of lethality in C. elegans lacking CUP-5, the Mucolipidosis Type IV orthologue. 1653 Jul 47

Although traditionally regarded as a cellular adaptive process triggered by nutrient deprivation, autophagy in neurons appears to provide an important neuroprotective mechanism. Neurons in the brain are protected from starvation, and neuronal autophagy serves a critical role in the turnover of abnormal proteins and damaged organelles. As post-mitotic, highly polarized cells with active protein trafficking, neurons rely heavily on an efficient autophagic pathway. Using human embryonic stem cell-derived neurons engineered to mimic the cholesterol lysosomal storage disease Niemann Pick type C1 (NPC1), we have shown that excessive activation and impaired progression of the autophagic pathway conspire to cause abnormal mitochondrial clearance. Defective mitophagy is exceptionally severe in human NPC1 neurons, as compared with patient fibroblasts, and may explain the selective neuronal failure observed in NPC1 and related neurodegenerative disorders.
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PMID:Defective mitophagy in human Niemann-Pick Type C1 neurons is due to abnormal autophagy activation. 2243 40

Lysosomes play a central role in regulating autophagy via activation of mammalian target of rapamycin complex 1 (mTORC1). We examined mTORC1 signalling in the lysosomal storage disease nephropathic cystinosis (MIM 219800), in which accumulation of autophagy markers has been previously demonstrated. Cystinosis is caused by mutations in the lysosomal cystine transporter cystinosin and initially affects kidney proximal tubules causing renal Fanconi syndrome, followed by a gradual development of end-stage renal disease and extrarenal complications. Using proximal tubular kidney cells obtained from healthy donors and from cystinotic patients, we demonstrate that cystinosin deficiency is associated with a perturbed mTORC1 signalling, delayed reactivation of mTORC1 after starvation and abnormal lysosomal retention of mTOR during starvation. These effects could not be reversed by treatment with cystine-depleting drug cysteamine. Altered mTORC1 signalling can contribute to the development of proximal tubular dysfunction in cystinosis and points to new possibilities in therapeutic intervention through modulation of mTORC-dependent signalling cascades.
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PMID:Altered mTOR signalling in nephropathic cystinosis. 2690 99

Lysosomal storage disorders are characterized by progressive accumulation of undigested macromolecules within the cell due to lysosomal dysfunction. 573C10 is a Schwann cell line derived from a mouse model of Niemann-Pick type C disease-1, NPC (-/-). Under serum-starved conditions, NPC (-/-) cells manifested impaired autophagy accompanied by an increase in the amount of p62 and lysosome enlargement. Addition of L-leucine to serum-starved NPC (-/-) cells ameliorated the enlargement of lysosomes and the p62 accumulation. Similar autophagy defects were observed in NPC (-/-) cells even without serum starvation upon the knockdown of Spinster-like 1 (SPNS1), a putative transporter protein thought to function in lysosomal recycling. Conversely, SPNS1 overexpression impeded the enlargement of lysosomes, p62 accumulation and mislocalization of the phosphorylated form of the mechanistic Target of rapamycin in NPC (-/-) cells. In addition, we found a reduction in endogenous SPNS1 expression in fibroblasts derived from NPC-1 patients compared with normal fibroblasts. We propose that SPNS1-dependent L-leucine export across the lysosomal membrane is a key step for triggering autophagy, and that this mechanism is impaired in NPC-1.
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PMID:L-leucine and SPNS1 coordinately ameliorate dysfunction of autophagy in mouse and human Niemann-Pick type C disease. 2916 37