Identification of Polycystin-1 interacting proteins
Ontology highlight
ABSTRACT:
INSTRUMENT(S):
ORGANISM(S): Homo Sapiens (human)
TISSUE(S): Cell Culture
SUBMITTER: 
Tilman Busch
LAB HEAD: Michael Koettgen
PROVIDER: PXD056889 | Pride | 2024-11-12
REPOSITORIES: Pride
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| PC1.zip | Other | |||
| PC1_Search.xml | Xml | |||
| checksum.txt | Txt |
Items per page: 5 1 - 3 of 3 |
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Project description:Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent potentially lethal monogenic disorder. Mutations in the PKD1 gene, which encodes polycystin-1 (PC1), account for approximately 78% of cases. PC1 is a large 462-kDa protein that undergoes cleavage in its N and C-terminal domains. C-terminal cleavage produces fragments that translocate to mitochondria. We show that transgenic expression of a protein corresponding to the final 200 amino acid (aa) residues of PC1 in two Pkd1-KO orthologous murine models of ADPKD suppresses cystic phenotype and preserves renal function. This suppression depends upon an interaction between the C-terminal tail of PC1 and the mitochondrial enzyme Nicotinamide Nucleotide Transhydrogenase (NNT). This interaction modulates tubular/cyst cell proliferation, the metabolic profile, mitochondrial function, and the redox state. Together, these results suggest that a short fragment of PC1 is sufficient to suppress cystic phenotype and open the door to the exploration of gene therapy strategies for ADPKD.
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Project description:Mouse peritoneal B1a cells were classified into two groups based upon the expression level of PC1. One is PC1 high group and the other is PC1 low. To evaluate gene expression patterns that distinguished PC1 high expressing B1a cells from PC1 low expressing B1a cells, we used Affymetrix GeneChipM-BM-. Mouse gene 1.0 ST Array. FACS-sorted PC1 high and low cells from individual mouse were used for RNA extraction and Affyarray hybridization. There were six independent biological replications in each group - six cases of PC1 high cells and six cases of PC1 low cells.
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Project description:Autosomal dominant polycystic kidney disease (ADPKD) is a common cause of ESRD. Affected individuals inherit a defective copy of either the PKD1 or PKD2 gene, encoding the proteins polycystin?1 (PC1) or polycystin?2 (PC2) respectively. PC1 and PC2 are secreted on urinary exosome?like vesicles (ELVs) (100nm diameter vesicles), where PC1 is present in a cleaved form and may be complexed with PC2. Label free quantitative proteomic studies of urine ELVs in an initial discovery cohort (13 PKD1 and 18 Normals), revealed that of 2008 ELV proteins, nine (0.32%) showed a statistically significant difference between PKD1 and normals at a p<0.025. PC1 was reduced to 54% of the normal level (p<0.02) and PC2 reduced to 53% (p<0.001). TMEM2, a protein with homology to fibrocystin, the product of the polycystic hepatic and kidney disease (PKHD1) gene, is increased 2.1 fold (p<0.025). The PC1/TMEM2 ratio correlated inversely with height adjusted total kidney volume (HtTKV) in the discovery cohort and the ratio of PC1/TMEM2 or PC2/TMEM2 could be used to distinguish PKD1 from normals in a confirmation cohort. In summary, this study suggests that a test based on the urine exosomal PC1/TMEM2 or PC2/TMEM2 ratio may have utility in the diagnosis and perhaps monitoring of PKD1.
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