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Loss of the centrosomal protein ALMS1 alters lipid metabolism and the regulation of extracellular matrix-related processes

View ORCID ProfileBrais Bea-Mascato, Eduardo Gómez-Castañeda, Yara E. Sánchez-Corrales, View ORCID ProfileSergi Castellano, View ORCID ProfileDiana Valverde
doi: https://doi.org/10.1101/2022.11.02.514847
Brais Bea-Mascato
1CINBIO, Universidad de Vigo, 36310, Spain
2Grupo de Investigación en Enfermedades Raras y Medicina Pediátrica, Instituto de Investigación Sanitaria Galicia Sur (IIS Galicia Sur), SERGAS-UVIGO, Vigo, Spain
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Eduardo Gómez-Castañeda
4Molecular and Cellular Immunology Section, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
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Yara E. Sánchez-Corrales
3Genetics and Genomic Medicine Department, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
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Sergi Castellano
3Genetics and Genomic Medicine Department, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
5UCL Genomics, Zayed Centre for Research into Rare Disease in Children, University College London, London, United Kingdom
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Diana Valverde
1CINBIO, Universidad de Vigo, 36310, Spain
2Grupo de Investigación en Enfermedades Raras y Medicina Pediátrica, Instituto de Investigación Sanitaria Galicia Sur (IIS Galicia Sur), SERGAS-UVIGO, Vigo, Spain
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ABSTRACT

Background Alström syndrome (ALMS) is a rare autosomal recessive disease that is associated with mutations in ALMS1 gene. The main clinical manifestations of ALMS are retinal dystrophy, obesity, type 2 diabetes mellitus, dilated cardiomyopathy and multi-organ fibrosis, characteristic in kidneys and liver. Depletion of the protein encoded by ALMS1 has been associated with the alteration of different processes regulated via the primary cilium, such as the NOTCH or TGF-β signalling pathways. However, the cellular impact of these deregulated pathways in the absence of ALMS1 remains unknown.

Methods In this study, we integrated RNA-seq and proteomic analysis to determine the gene expression profile of hTERT-BJ-5ta ALMS1 knockout fibroblasts after TGF-β stimulation. In addition, we studied alterations in cross-signalling between the TGF-β pathway and the AKT pathway in this cell line.

Results We found that ALMS1 depletion affects the TGF-β pathway and its cross-signalling with other pathways such as PI3K/AKT, EGFR1 or p53. In addition, alterations associated with ALMS1 depletion clustered around the processes of extracellular matrix regulation and lipid metabolism in both the transcriptome and proteome. By studying the enriched pathways of common genes differentially expressed in the transcriptome and proteome, collagen fibril organisation, β-oxidation of fatty acids and eicosanoid metabolism emerged as key processes altered by the absence of ALMS1. Finally, an overactivation of the AKT pathway was determined in the absence of ALMS1 that could be explained by a decrease in PTEN gene expression.

Conclusion ALMS1 deficiency disrupts cross-signalling between the TGF-β pathway and other dependent pathways in hTERT-BJ-5ta cells. Furthermore, altered cross-signalling impacts the regulation of extracellular matrix-related processes and fatty acid metabolism, and leads to over-activation of the AKT pathway.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted November 02, 2022.
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Loss of the centrosomal protein ALMS1 alters lipid metabolism and the regulation of extracellular matrix-related processes
Brais Bea-Mascato, Eduardo Gómez-Castañeda, Yara E. Sánchez-Corrales, Sergi Castellano, Diana Valverde
bioRxiv 2022.11.02.514847; doi: https://doi.org/10.1101/2022.11.02.514847
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Loss of the centrosomal protein ALMS1 alters lipid metabolism and the regulation of extracellular matrix-related processes
Brais Bea-Mascato, Eduardo Gómez-Castañeda, Yara E. Sánchez-Corrales, Sergi Castellano, Diana Valverde
bioRxiv 2022.11.02.514847; doi: https://doi.org/10.1101/2022.11.02.514847

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