Browsing by Author "Rebolledo-Jaramillo, Boris"

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    A 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.
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    Identification 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.
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    Prodromal manifestations of Parkinson’s disease in adults with 22q11.2 microdeletion syndrome
    (2022) Juri, Carlos; Chaná-Cuevas, Pedro; Kramer, Vasko; Fritsch, Rosemarie; Ornstein, Claudia; Cuiza, Analía; Hernández, Carlos; Villanueva, Katiuska; Cordova, Teresa; Mauro, Jorge; Ocampo, Adrián; Rebolledo-Jaramillo, Boris; Repetto, Gabriela M.
    22q11.2 microdeletion syndrome (22qDS) was recently identified as a risk factor for development of early-onset Parkinson´s disease (PD). The classical motor manifestations of this disease are preceded by early signs and symptoms of neurodegeneration. The progression of 22qDS-associated PD is unknown. We aimed to evaluate the presence of prodromal PD in a group of adults with 22qDS using the Movement Disorders Society (MDS) Criteria for Prodromal PD. Thirty-eight persons with 22qDS and 13 age-matched controls participated in the study, and their results were compared using the MannWhitney U test. Persons with 22qDS had lower scores on olfaction testing (p=7.42Ex10-5), higher scores on the COMPASS 31 scale for dysautonomia (p=2.28x10-3) and on the motor evaluation using Movement Disorder Society (MDS)-sponsored revision of Unified Parkinson’s Disease Rating Scale motor subscore (UPDRS-III) (p=1.84x10-4), compared with healthy controls. Home polysomnogram did not find participants with REM-sleep behavior disorder. Integrity of nigrostriatal dopaminergic system was evaluated by PET-CT imaging of presynaptic dopamine with 18F-PR04.MZ. Patients showed significantly higher specific binding ratios in the striatum, compared to controls (p=9.57x10-3 at the caudate nuclei). Two patients with 22qDS (5.2%) had decreased uptake in the posterior putamen (less than 60% of controls) and one fulfilled MDS criteria for prodromal PD. These results show that patients with 22qDS manifest some signs and symptoms of prodromal PD such as hyposmia, dysautonomia and mild movement alterations. In the majority, this was associated with elevated dopaminergic signaling, suggesting that loss of dopaminergic neurons may not be the cause. A smaller subgroup did show evidence of a decrease in nigrostriatal dopaminergic signaling, as seen in classical prodromal PD. Longitudinal studies are necessary to understand the progression to and risk of PD in persons with 22qDS.