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Project Title
Discovery of a Novel TFEB Regulation Pathway by the c-Abl Kinase Reveals a Common Therapeutic Approach for Sphingolipidosis
Partner Organisations
Internal ID
1190334
Principal Investigator
Silvana Zanlungo
Start Date
2018

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Publication

Complement Component C3 Participates in Early Stages of Niemann–Pick C Mouse Liver Damage

2020 , Andrés D. Klein , Javier González de la Vega , Silvana Zanlungo

Niemann–Pick type C (NPC), a lysosomal storage disorder, is mainly caused by mutations in the NPC1 gene. Niemann–Pick type C patients and mice show intracellular cholesterol accumulation leading to hepatic failure with increased inflammatory response. The complement cascade, which belongs to the innate immunity response, recognizes danger signals from injured tissues. We aimed to determine whether there is activation of the complement system in the liver of the NPC mouse and to assess the relationship between C3 activation, a final component of the pathway, and NPC liver pathology. Niemann–Pick type C mice showed high levels of C3 staining in the liver which unexpectedly decreased with aging. Using an inducible NPC1 hepatocyte rescue mouse model, we restored NPC1 expression for a short time in young mice. We found C3 positive cells only in non-rescued cells, suggesting that C3 activation in NPC cells is reversible. Then, we studied the effect of C3 ablation on NPC liver damage at two postnatal time points, P56 and P72. Deletion of C3 reduced the presence of hepatic CD68-positive cells at postnatal day 56 and prevented the increase of transaminase levels in the blood of NPC mice. These positive effects were abrogated at P72, indicating that the complement cascade participates only during the early stages of liver damage in NPC mice, and that its inhibition may serve as a new potential therapeutic strategy for the disease.

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Publication

Proteomic Analysis of Niemann-Pick Type C Hepatocytes Reveals Potential Therapeutic Targets for Liver Damage

2021 , Elisa Balboa , Tamara Marín , Juan Esteban Oyarzún , Pablo S. Contreras , Robert Hardt , Thea van den Bosch , Alejandra R. Alvarez , Boris Rebolledo-Jaramillo , Andres D. Klein , Dominic Winter , Silvana Zanlungo

Niemann-Pick type C disease (NPCD) is a lysosomal storage disorder caused by mutations in the NPC1 gene. The most affected tissues are the central nervous system and liver, and while significant efforts have been made to understand its neurological component, the pathophysiology of the liver damage remains unclear. In this study, hepatocytes derived from wild type and Npc1−/− mice were analyzed by mass spectrometry (MS)-based proteomics in conjunction with bioinformatic analysis. We identified 3832 proteins: 416 proteins had a p-value smaller than 0.05, of which 37% (n = 155) were considered differentially expressed proteins (DEPs), 149 of them were considered upregulated, and 6 were considered downregulated. We focused the analysis on pathways related to NPC pathogenic mechanisms, finding that the most significant changes in expression levels occur in proteins that function in the pathways of liver damage, lipid metabolism, and inflammation. Moreover, in the group of DEPs, 30% (n = 47) were identified as lysosomal proteins and 7% (n = 10) were identified as mitochondrial proteins. Importantly, we found that lysosomal DEPs, including CTSB/D/Z, LIPA, DPP7 and GLMP, and mitocondrial DEPs, AKR1B10, and VAT1 had been connected with liver fibrosis, damage, and steatosis in previous studies, validiting our dataset. Our study found potential therapeutic targets for the treatment of liver damage in NPCD.

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Publication

c-Abl Inhibition Activates TFEB and Promotes Cellular Clearance in a Lysosomal Disorder

2020 , Pablo S. Contreras , Pablo J. Tapia , Lila González-Hódar , Ivana Peluso , Chiara Soldati , Gennaro Napolitano , Maria Matarese , Macarena Las Heras , Cristian Valls , Alexis Martinez , Elisa Balboa , Juan Castro , Nancy Leal , Frances M. Platt , Andrzej Sobota , Dominic Winter , KLEIN POSTERNACK, ANDRES DAVID , Diego L. Medina , Andrea Ballabio , Alejandra R. Alvarez , Silvana Zanlungo

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Publication

A Mouse Systems Genetics Approach Reveals Common and Uncommon Genetic Modifiers of Hepatic Lysosomal Enzyme Activities and Glycosphingolipids

2023 , Anyelo Durán , David A. Priestman , Macarena Las Las Heras , Boris Rebolledo-Jaramillo , Valeria Olguín , CALDERON GIADROSIC, JUAN FRANCISCO , Silvana Zanlungo , Jaime Gutiérrez , Frances M. Platt , Andrés D. Klein

Identification of genetic modulators of lysosomal enzyme activities and glycosphingolipids (GSLs) may facilitate the development of therapeutics for diseases in which they participate, including Lysosomal Storage Disorders (LSDs). To this end, we used a systems genetics approach: we measured 11 hepatic lysosomal enzymes and many of their natural substrates (GSLs), followed by modifier gene mapping by GWAS and transcriptomics associations in a panel of inbred strains. Unexpectedly, most GSLs showed no association between their levels and the enzyme activity that catabolizes them. Genomic mapping identified 30 shared predicted modifier genes between the enzymes and GSLs, which are clustered in three pathways and are associated with other diseases. Surprisingly, they are regulated by ten common transcription factors, and their majority by miRNA-340p. In conclusion, we have identified novel regulators of GSL metabolism, which may serve as therapeutic targets for LSDs and may suggest the involvement of GSL metabolism in other pathologies.

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Publication

c-Abl activates RIPK3 signaling in Gaucher disease

2021 , M.J. Yañez , F. Campos , T. Marín , A.D. Klein , A.H. Futerman , A.R. Alvarez , S. Zanlungo

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Publication

Identification of genetic modifiers of murine hepatic β-glucocerebrosidase activity

2021 , Anyelo Durán , Boris Rebolledo-Jaramillo , Valeria Olguin , Marcelo Rojas-Herrera , Macarena Las Heras , CALDERON GIADROSIC, JUAN FRANCISCO , Silvana Zanlungo , David A. Priestman , Frances M. Platt , KLEIN POSTERNACK, ANDRES DAVID

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