Browsing by Author "Klein, Andres D."
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- ItemA Mouse Systems Genetics Approach Reveals Common and Uncommon Genetic Modifiers of Hepatic Lysosomal Enzyme Activities and Glycosphingolipids(2023) Duran, Anyelo; Priestman, David A.; Las Heras, Macarena; Rebolledo-Jaramillo, Boris; Olguin, Valeria; Calderon, Juan F.; Zanlungo, Silvana; Gutierrez, Jaime; Platt, Frances M.; Klein, Andres D.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.
- ItemGadolinium chloride rescues niemann-pick type C liver damage(2018) Klein, Andres D.; Oyarzún Isamitt, Juan Esteban; Cortez, Cristian; Zanlungo Matsuhiro, Silvana
- ItemIdentification of genetic modifiers of murine hepatic β-glucocerebrosidase activity(2021) Duran, Anyelo; Rebolledo-Jaramillo, Boris; Olguin, Valeria; Rojas-Herrera, Marcelo; Heras, Macarena Las; Calderon, Juan F.; Zanlungo, Silvana; Priestman, David A.; Platt, Frances M.; Klein, Andres D.The acid beta-glucocerebrosidase (GCase) enzyme cleaves glucosylceramide into glucose and ceramide. Loss of function variants in the gene encoding for GCase can lead to Gaucher disease and Parkinson's disease. Therapeutic strategies aimed at increasing GCase activity by targeting a modulating factor are attractive and poorly explored. To identify genetic modifiers, we measured hepatic GCase activity in 27 inbred mouse strains. A genome-wide association study (GWAS) using GCase activity as a trait identified several candidate modifier genes, including Dmrtc2 and Arhgef1 (p=2.1x10(-7)), and Grik5 (p=2.1x10(-7)). Bayesian integration of the gene mapping with transcriptomics was used to build integrative networks. The analysis uncovered additional candidate GCase regulators, highlighting modules of the acute phase response (p=1.01x10(-8)), acute inflammatory response (p=1.01x10(-8)), fatty acid beta-oxidation (p=7.43x10(-5)), among others. Our study revealed previously unknown candidate modulators of GCase activity, which may facilitate the design of therapies for diseases with GCase dysfunction.
- ItemNpc1 deficiency in the C57BL/6J genetic background enhances Niemann–Pick disease type C spleen pathology(2011) Parra Cares, Julio Alejandro; Klein, Andres D.; Castro, Juan Francisco; Morales France, María Gabriela; Mosqueira Montero, Matías José; Valencia Araya, Ilse; Cortés Mora, Víctor Antonio; Rigotti Rivera, Attilio; Zanlungo Matsuhiro, SilvanaNiemann–Pick type C (NPC) disease is an autosomal recessive neurovisceral lipid storage disorder. The affected genes are NPC1 and NPC2. Mutations in either gene lead to intracellular cholesterol accumulation. There are three forms of the disease, which are categorized based on the onset and severity of the disease: the infantile form, in which the liver and spleen are severely affected, the juvenile form, in which the liver and brain are affected, and the adult form, which affects the brain. In mice, a spontaneous mutation in the Npc1 gene originated in the BALB/c inbred strain mimics the juvenile form of the disease. To study the influence of genetic background on the expression of NPC disease in mice, we transferred the Npc1 mutation from the BALB/c to C57BL/6J inbred background. We found that C57BL/6J-Npc1−/− mice present with a much more aggressive form of the disease, including a shorter lifespan than BALB/c-Npc1−/− mice. Surprisingly, there was no difference in the amount of cholesterol in the brains of Npc1−/− mice of either mouse strain. However, Npc1−/− mice with the C57BL/6J genetic background showed striking spleen damage with a marked buildup of cholesterol and phospholipids at an early age, which correlated with large foamy cell clusters. In addition, C57BL/6J Npc1−/− mice presented red cell abnormalities and abundant ghost erythrocytes that correlated with a lower hemoglobin concentration. We also found abnormalities in white cells, such as cytoplasmic granulation and neutrophil hypersegmentation that included lymphopenia and atypias. In conclusion, Npc1 deficiency in the C57BL6/J background is associated with spleen, erythrocyte, and immune system abnormalities that lead to a reduced lifespan.
- ItemProteomic Analysis of Niemann-Pick Type C Hepatocytes Reveals Potential Therapeutic Targets for Liver Damage(2021) Balboa Castillo, Elisa Ivana; Marín Marín, Tamara Alejandra; Oyarzún Isamitt, Juan Esteban; Contreras, Pablo S.; Hardt, Robert; Van Den Bosch, Thea; Álvarez Rojas, Alejandra; Rebolledo Jaramillo, Boris; Klein, Andres D.; Winter, Dominic; Zanlungo Matsuhiro, SilvanaNiemann-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.