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Understanding the phenotypic variability in Niemann-Pick disease type C (NPC): a need for precision medicine
(2023)
Macarena Las Heras
;
Benjamín Szenfeld
;
Rami A. Ballout
;
Emanuele Buratti
;
Silvana Zanlungo
<jats:title>Abstract</jats:title><jats:p>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 <jats:italic>NPC1</jats:italic> and <jats:italic>NPC2</jats:italic> 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.</jats:p>
Scopus© Citations 7 2
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Glucocerebrosidase mutations disrupt the lysosome and now the mitochondria
(2023)
Andrés D. Klein
;
Tiago Fleming Outeiro
1Scopus© Citations 19
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Lack of Annexin A6 Exacerbates Liver Dysfunction and Reduces Lifespan of Niemann-Pick Type C Protein–Deficient Mice
(2021)
Elsa Meneses-Salas
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Marta Garcia-Forn
;
Carla Castany-Pladevall
;
Albert Lu
;
Alba Fajardo
Scopus© Citations 3 5
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A Mouse Systems Genetics Approach Reveals Common and Uncommon Genetic Modifiers of Hepatic Lysosomal Enzyme Activities and Glycosphingolipids
(2023)
Anyelo Durán
;
David A. Priestman
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Macarena Las Las Heras
;
Boris Rebolledo-Jaramillo
;
Valeria Olguín
<jats:p>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.</jats:p>
1
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Genetic Background Matters: Population-Based Studies in Model Organisms for Translational Research
(2022)
Valeria Olguín
;
Anyelo Durán
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Macarena Las Heras
;
Juan Carlos Rubilar
;
Francisco A. Cubillos
<jats:p>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.</jats:p>
46Scopus© Citations 8
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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
<jats:p>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.</jats:p>
Scopus© Citations 14 2
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Role of proteases in dysfunctional placental vascular remodelling in preeclampsia
(2020)
Jaime A. Gutiérrez
;
Isabel Gómez
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Delia I. Chiarello
;
Rocío Salsoso
;
Andrés D. Klein
16Scopus© Citations 15

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