Browsing by Author "Las Heras, Macarena"

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    A Mouse Systems Genetics Approach Reveals Common and Uncommon Genetic Modifiers of Hepatic Lysosomal Enzyme Activities and Glycosphingolipids
    (2023) Durán, Anyelo; Priestman, David; Las Heras, Macarena; Rebolledo, Boris; Olguín, Valeria; Calderón, Juan; Zanlungo, Silvana; Gutiérrez, Jaime; Platt, Frances; Klein, Andrés
    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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    c-Abl Inhibition Activates TFEB and Promotes Cellular Clearance in a Lysosomal Disorder
    (Cell Press, 2020) Contreras, Pablo; Tapia, Pablo; González-Hodar, Lila; Peluso, Ivana; Soldati, Chiara; Napoiotano, Gennaro; Matarese, María; Las Heras, Macarena; Valls, Cristian; Martínez, Alexis; Balboa, Elisa; Castro, Juan; Nancy, Leal; Platt, Frances; Sobota, Andrzej; Winter, Dominic; Klein, Andrés; Medina, Diego; Ballabio, Andrea; Alvarez, Alejandra; Zanlungo, Silvana
    The transcription factor EB (TFEB) has emerged as a master regulator of lysosomal biogenesis, exocytosis, and autophagy, promoting the clearance of substrates stored in cells. c-Abl is a tyrosine kinase that participates in cellular signaling in physiological and pathophysiological conditions. In this study, we explored the connection between c-Abl and TFEB. Here, we show that under pharmacological and genetic c-Abl inhibition, TFEB translocates into the nucleus promoting the expression of its target genes independently of its well-known regulator, mammalian target of rapamycin complex 1. Active c-Abl induces TFEB phosphorylation on tyrosine and the inhibition of this kinase promotes lysosomal biogenesis, autophagy, and exocytosis. c-Abl inhibition in Niemann-Pick type C (NPC) models, a neurodegenerative disease characterized by cholesterol accumulation in lysosomes, promotes a cholesterol-lowering effect in a TFEB-dependent manner. Thus, c-Abl is a TFEB regulator that mediates its tyrosine phosphorylation, and the inhibition of c-Abl activates TFEB promoting cholesterol clearance in NPC models.
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    Genetic Background Matters: Population-Based Studies in Model Organisms for Translational Research
    (2022) Olguín, Valeria; Durán, Anyelo; Las Heras, Macarena; Rubilar, Juan; Cubillos, Francisco; Olguín, Patricio; Klein, Andrés
    We are all similar but a bit different. These differences are partially due to variations in our genomes and are related to the heterogeneity of symptoms and responses to treatments that patients exhibit. Most animal studies are performed in one single strain with one manipulation. However, due to the lack of variability, therapies are not always reproducible when treatments are translated to humans. Panels of already sequenced organisms are valuable tools for mimicking human phenotypic heterogeneities and gene mapping. This review summarizes the current knowledge of mouse, fly, and yeast panels with insightful applications for translational research.
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    Identification of genetic modifiers of murine hepatic β-glucocerebrosidase activity
    (2021) Durán, Anyelo; Rebolledo-Jaramillo, Boris; Olguin, Valeria; Rojas-Herrera, Marcelo; Las Heras, Macarena; Calderón, Juan F.; Zanlungo, Silvana; Priestman, David A.; Platt, Frances M.; Klein, Andrés
    The acid β-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.
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    Understanding the phenotypic variability in Niemann-Pick disease type C (NPC): a need for precision medicine
    (2023) Las Heras, Macarena; Szenfeld, Benjamín; Ballout, Rami A.; Buratti, Emanuele; Zanlungo, Silvana; Dardis, Andrea; KLEIN, ANDRES
    Niemann-Pick type C (NPC) disease is a lysosomal storage disease (LSD) characterized by the buildup of endo-lysosomal cholesterol and glycosphingolipids due to loss of function mutations in the NPC1 and NPC2 genes. NPC patients can present with a broad phenotypic spectrum, with differences at the age of onset, rate of progression, severity, organs involved, effects on the central nervous system, and even response to pharmacological treatments. This article reviews the phenotypic variation of NPC and discusses its possible causes, such as the remaining function of the defective protein, modifier genes, sex, environmental cues, and splicing factors, among others. We propose that these factors should be considered when designing or repurposing treatments for this disease. Despite its seeming complexity, this proposition is not far-fetched, considering the expanding interest in precision medicine and easier access to multi-omics technologies.

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