Autosomal Dominant Polycystic Kidney Disease: Is There a Role for Autophagy?

Ponticelli, Claudio; Moroni, Gabriella; Reggiani, Francesco

doi:10.3390/ijms241914666

Cited by 3 publications

(1 citation statement)

References 109 publications

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“…Autophagy and apoptosis are critical for the functional integrity of organs and cells under normal and pathological conditions and, although distinctly regulated, can be closely related [38]. One central finding of our study is that autophagy is reduced, while apoptosis, upon oxidative stress, is increased in R236C-expressing cells.…”

Section: Discussionmentioning

confidence: 67%

Molecular determinants of SEC61A1 mutant R236C in two patient-derived cellular platforms

Weiand,

Sandfort,

Nadzemova

et al. 2023

Preprint

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Background & objectivesSEC61A1 encodes a central protein of the mammalian translocon machinery residing in the ER. Mutations ofSEC61A1are implicated to result in various severe diseases. Recently, mutation R236C was identified in patients having autosomal dominant polycystic liver disease (ADPLD), which originates from defects of cholangiocytes in the liver. The molecular phenotype of R236C was assessed.MethodsTwo cellular platforms were established from the same cell source of an ADPLD patient by different methodology. Cells were immortalized by retroviral transduction of an oncogene (UCi) or reprogrammed to induced pluripotent stem cells (iPSC) that were differentiated to cholangiocyte progenitor-like cells (CPLC). UCi and CPLC were subjected to several analyses of molecular pathways that were previously associated with development of polycystic disease.ResultsUCi displayed markers of epithelial cells, while CPLCs expressed typical markers of both cholangiocytes and hepatocytes. Cells encoding R236C showed a stable, continuous proliferation in both platforms, however growth rates were reduced as compared to wildtype control. Autophagy, cAMP synthesis, and secretion of important marker proteins were reduced in R236C-expressing cells. In addition, R236C induced increased calcium leakiness from the ER to the cytoplasm. Upon oxidative stress, R236C led to a high induction of apoptosis and necrosis.ConclusionAlthough the grade of aberrant cellular functions differed between the two platforms, overall the molecular phenotype of R236C was shared suggesting that the mutation, regardless of the cell type, has a dominant impact on disease-associated pathways that cause ADPLD. Our approach may be valuable to decipher the molecular pathways of other rare genetic diseases using patient-specific cell models.

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Section: Discussionmentioning

confidence: 67%

Molecular determinants of SEC61A1 mutant R236C in two patient-derived cellular platforms

Weiand,

Sandfort,

Nadzemova

et al. 2023

Preprint

View full text Add to dashboard Cite

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Comparative analysis of SEC61A1 mutant R236C in two patient-derived cellular platforms

Weiand,

Sandfort,

Nadzemova

et al. 2024

Sci Rep

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SEC61A1 encodes a central protein of the mammalian translocon and dysfunction results in severe disease. Recently, mutation R236C was identified in patients having autosomal dominant polycystic liver disease (ADPLD). The molecular phenotype of R236C was assessed in two cellular platforms. Cells were immortalized by retroviral transduction of an oncogene (UCi) or reprogrammed to induced pluripotent stem cells (iPSC) that were differentiated to cholangiocyte progenitor-like cells (CPLC). UCi and CPLC were subjected to analyses of molecular pathways that were associated with development of disease. UCi displayed markers of epithelial cells, while CPLCs expressed typical markers of both cholangiocytes and hepatocytes. Cells encoding R236C showed a stable, continuous proliferation in both platforms, however growth rates were reduced as compared to wildtype control. Autophagy, cAMP synthesis, and secretion of important marker proteins were reduced in R236C-expressing cells. In addition, R236C induced increased calcium leakiness from the ER to the cytoplasm. Upon oxidative stress, R236C led to a high induction of apoptosis and necrosis. Although the grade of aberrant cellular functions differed between the two platforms, the molecular phenotype of R236C was shared suggesting that the mutation, regardless of the cell type, has a dominant impact on disease-associated pathways.

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Role of MicroRNAs in Autosomal Dominant Polycystic Kidney Disease: Expression Profiles and Pathway Analysis

Devi,

Ranjan,

Mishra

et al. 2024

Preprint

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This study investigates the role of specific microRNAs (miRNAs) in autosomal dominant polycystic kidney disease (ADPKD). Network analysis using Cytoscape 3.10.1 revealed 28 miRNAs that target two or more PKD related genes, while 14 miRNAs interacted with three or more genes. Pathway analysis of these 14 miRNAs, conducted via the miRPath V4.0 tool, utilized various resources such as KEGG, GO terms, Pfam, and MSigDB, highlighting their functional roles in ADPKD. Among these 14 miRNAs, four were prioritized for further analysis based on the higher number of target genes and existing evidence of their expression in blood. These miRNAs were analyzed for fold change expression levels using qRT-PCR on blood-derived RNA samples from ADPKD patients (n=19) and healthy controls (n=5). These four miRNAs - hsa-miR20a-5p, hsa-miR27b-3p, hsa-miR3613-3p, and hsa-miR181a-5p - showed significant upregulation with p-values of 0.0179, 0.0002, 0.0166, and 0.0402 respectively. The functional enrichment of miRNAs involved in PKD evidently suggests that these play diverse roles in regulating key processes such as cell cycle progression, mTOR signaling, autophagy, EMT, and cellular responses to hypoxia thus playing crucial role in the pathogenesis of ADPKD and could serve as potential biomarkers or therapeutic targets.

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Autosomal Dominant Polycystic Kidney Disease: Is There a Role for Autophagy?

Cited by 3 publications

References 109 publications

Molecular determinants of SEC61A1 mutant R236C in two patient-derived cellular platforms

Molecular determinants of SEC61A1 mutant R236C in two patient-derived cellular platforms

Comparative analysis of SEC61A1 mutant R236C in two patient-derived cellular platforms

Role of MicroRNAs in Autosomal Dominant Polycystic Kidney Disease: Expression Profiles and Pathway Analysis

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