Dataset Information

Characterization of Zebrafish Models of Marinesco-Sjogren Syndrome.

ABSTRACT: SIL1 is a nucleotide exchange factor for the endoplasmic reticulum chaperone, BiP. Mutations in the SIL1 gene cause Marinesco-Sjögren syndrome (MSS), an autosomal recessive disease characterized by cerebellar ataxia, mental retardation, congenital cataracts, and myopathy. To create novel zebrafish models of MSS for therapeutic drug screening, we analyzed phenotypes in sil1 knock down fish by two different antisense oligo morpholinos. Both sil1 morphants had abnormal formation of muscle fibers and irregularity of the myosepta. Moreover, they showed smaller-sized eyes and loss of purkinje cells in cerebellar area compared to controls. Immunoblotting analysis revealed increased protein amounts of BiP, lipidated LC3, and caspase 3. These data supported that the sil1 morphants can represent mimicking phenotypes of human MSS. The sil1 morphants phenocopy the human MSS disease pathology and are a good animal model for therapeutic studies.

SUBMITTER: Kawahara G

PROVIDER: S-EPMC5085058 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Characterization of Zebrafish Models of Marinesco-Sjögren Syndrome.

Kawahara Genri G Hayashi Yukiko K YK

PloS one 20161028 10

SIL1 is a nucleotide exchange factor for the endoplasmic reticulum chaperone, BiP. Mutations in the SIL1 gene cause Marinesco-Sjögren syndrome (MSS), an autosomal recessive disease characterized by cerebellar ataxia, mental retardation, congenital cataracts, and myopathy. To create novel zebrafish models of MSS for therapeutic drug screening, we analyzed phenotypes in sil1 knock down fish by two different antisense oligo morpholinos. Both sil1 morphants had abnormal formation of muscle fibers an ...[more]

PMID: 27792754

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Project description:Marinesco-Sjogren syndrome (MSS) is a rare multisystem pediatric disorder, caused by loss of function of the endoplasmic reticulum cochaperone SIL1 in about 60% of the patients. SIL1 acts as a nucleotide exchange factor for BiP, which plays a central role in secretory protein folding. SIL1-deficient cells have reduced BiP-assisted protein folding, cannot fulfil their protein needs and experience chronic activation of the unfolded protein response (UPR). Maladaptive UPR may explain the cerebellar and skeletal muscle degeneration re-sponsible for the ataxia and muscle weakness typical of MSS. However, the cause of other, more variable, clinical manifestations, such as mild to severe mental retardation, hypogonadism, short stature and skeletal deformities, are less clear. To gain insights into the pathogenic mechanisms of MSS, we carried out cell bio-logical and proteomic investigations in skin fibroblasts derived from a young patient carrying the SIL1 ... mutation. Despite fibroblasts are not overtly affected in MSS we found morphological and biochemical changes consistent with UPR and metabolic alterations. All the cell machineries involved in RNA splicing and translation were strongly downregulated, while protein degradation via lysosome-based structures was boosted, consistent with an attempt of the cell to reduce the workload of the endoplasmic reticulum and dis-pose misfolded proteins. Cell metabolism was extensively affected as we observed a reduction in lipid syn-thesis, an increase in beta oxidation and an enhancement of the tricarboxylic acid cycle, with upregulation of eight of its enzymes. Finally, the catabolic pathways of various amino acids, including valine, leucine, isoleu-cine, tryptophane, lysine, aspartate and phenylalanine, were enhanced, while the biosynthetic pathways of arginine, serine, glycine and cysteine were reduced. These results indicate profound metabolic alterations in MSS cells in addition to UPR activation and increased protein degradation, which may contribute to make them resistant to SIL1 loss.

Dataset Information

Characterization of Zebrafish Models of Marinesco-Sjogren Syndrome.

Publications

Characterization of Zebrafish Models of Marinesco-Sjögren Syndrome.

Similar Datasets

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