Browsing by Author "Platt, Frances"

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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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