Dataset Information

Alteration of the unfolded protein response modifies neurodegeneration in a mouse model of Marinesco-Sjogren syndrome.

ABSTRACT: Endoplasmic reticulum (ER) stress has been linked to the onset and progression of many diseases. SIL1 is an adenine nucleotide exchange factor of the essential ER lumen chaperone HSPA5/BiP that senses ER stress and is involved in protein folding. Mutations in the Sil1 gene have been associated with Marinesco-Sjögren syndrome, hallmarks of which include ataxia and cerebellar atrophy. We have previously shown that loss of SIL1 function in mouse results in ER stress, ubiquitylated protein inclusions, and degeneration of specific Purkinje cells in the cerebellum. Here, we report that overexpression of HYOU1/ORP150, an exchange factor that works in parallel to SIL1, prevents ER stress and rescues neurodegeneration in Sil1(-/-) mice, whereas decreasing expression of HYOU1 exacerbates these phenotypes. In addition, loss of DNAJC3/p58(IPK), a co-chaperone that promotes ATP hydrolysis by BiP, ameliorates ER stress and neurodegeneration in Sil1(-/-) mice. These findings suggest that alterations in the nucleotide exchange cycle of BiP cause ER stress and neurodegeneration in Sil1-deficient mice. Our results present the first evidence of important genetic modifiers of Marinesco-Sjögren syndrome, and provide additional pathways for therapeutic intervention for this, and other ER stress-induced, diseases.

SUBMITTER: Zhao L

PROVIDER: S-EPMC2792147 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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Alteration of the unfolded protein response modifies neurodegeneration in a mouse model of Marinesco-Sjögren syndrome.

Zhao Lihong L Rosales Christine C Seburn Kevin K Ron David D Ackerman Susan L SL

Human molecular genetics 20100101 1

Endoplasmic reticulum (ER) stress has been linked to the onset and progression of many diseases. SIL1 is an adenine nucleotide exchange factor of the essential ER lumen chaperone HSPA5/BiP that senses ER stress and is involved in protein folding. Mutations in the Sil1 gene have been associated with Marinesco-Sjögren syndrome, hallmarks of which include ataxia and cerebellar atrophy. We have previously shown that loss of SIL1 function in mouse results in ER stress, ubiquitylated protein inclusion ...[more]

PMID: 19801575

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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

Alteration of the unfolded protein response modifies neurodegeneration in a mouse model of Marinesco-Sjogren syndrome.

Publications

Alteration of the unfolded protein response modifies neurodegeneration in a mouse model of Marinesco-Sjögren syndrome.

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