CRIS

Permanent URI for this communityhttps://investigadores.udd.cl/handle/123456789/1

Browse

Settings

Access type: UnknownAuthor: search.filters.author.Juan Carlos Rubilar

Search Results

Now showing 1 - 5 of 5
  • Loading...
    Thumbnail Image
    Some of the metrics are blocked by your 
    consent settings
    Item type:Publication,
    Modifier gene identification reveals therapeutic pathways for adult and childhood dementias
    (Springer Science and Business Media LLC, 2026-02-16)
    Benjamín Szenfeld
    ;
    Macarena Las Heras
    ;
    Juan Carlos Rubilar
    ;
    Leah Skura
    ;
    Jorge Olivares
      2
  • Loading...
    Thumbnail Image
    Some of the metrics are blocked by your 
    consent settings
    Item type:Publication,
      1
  • Loading...
    Thumbnail Image
    Some of the metrics are blocked by your 
    consent settings
    Item type:Publication,
    Genomic modifiers of neurological resilience in a Niemann‐Pick C family
    (Wiley, 2025-06-12)
    Macarena Las Heras
    ;
    Benjamín Szenfeld
    ;
    Valeria Olguín
    ;
    Juan Carlos Rubilar
    ;
    CALDERON GIADROSIC, JUAN FRANCISCO  
    Niemann-Pick type C (NPC) disease, caused by NPC1 or NPC2 variants, disrupts cholesterol and glycolipid trafficking, leading to diverse clinical manifestations. To understand the genetic basis of neurological resilience, we analyzed an NPC family with variable phenotypes, identifying loss-of-function variants in CCDC115, SLC4A5, DEPDC5, ETFDH, SNRNP200, and DOCK1 that co-segregated with milder neurological involvement. Using yeast models, we successfully predicted NPC-like severity based on orthologous gene variants. RNA-seq revealed a positive correlation between mitochondrial transcripts and cellular fitness. Modeling NPC in yeast lacking the SLC4A5 ortholog, bor1, enhanced cellular fitness, improved mitochondrial function, and reduced sterol accumulation. Our findings identify potential modifiers and biomarkers of NPC severity, highlighting mitochondrial pathways and SLC4A5 as a therapeutic target.
      6
  • Loading...
    Thumbnail Image
    Some of the metrics are blocked by your 
    consent settings
    Item type:Publication,
    The lysosomal β-glucocerebrosidase strikes mitochondria: implications for Parkinson’s therapeutics
    (2024)
    Juan Carlos Rubilar
    ;
    Tiago Fleming Outeiro
    ;
    KLEIN POSTERNACK, ANDRES DAVID  
    <jats:title>Abstract</jats:title> <jats:p>Parkinson’s disease is a neurodegenerative disorder primarily known for typical motor features that arise due to the loss of dopaminergic neurons in the substantia nigra. However, the precise molecular aetiology of the disease is still unclear. Several cellular pathways have been linked to Parkinson’s disease, including the autophagy-lysosome pathway, α-synuclein aggregation and mitochondrial function. Interestingly, the mechanistic link between GBA1, the gene that encodes for lysosomal β-glucocerebrosidase (GCase), and Parkinson’s disease lies in the interplay between GCase functions in the lysosome and mitochondria. GCase mutations alter mitochondria-lysosome contact sites. In the lysosome, reduced GCase activity leads to glycosphingolipid build-up, disrupting lysosomal function and autophagy, thereby triggering α-synuclein accumulation. Additionally, α-synuclein aggregates reduce GCase activity, creating a self-perpetuating cycle of lysosomal dysfunction and α-synuclein accumulation. GCase can also be imported into the mitochondria, where it promotes the integrity and function of mitochondrial complex I. Thus, GCase mutations that impair its normal function increase oxidative stress in mitochondria, the compartment where dopamine is oxidized. In turn, the accumulation of oxidized dopamine adducts further impairs GCase activity, creating a second cycle of GCase dysfunction. The oxidative state triggered by GCase dysfunction can also induce mitochondrial DNA damage which, in turn, can cause dopaminergic cell death. In this review, we highlight the pivotal role of GCase in Parkinson’s disease pathogenesis and discuss promising examples of GCase-based therapeutics, such as gene and enzyme replacement therapies, small molecule chaperones and substrate reduction therapies, among others, as potential therapeutic interventions.</jats:p>
      1Scopus© Citations 22
  • Loading...
    Thumbnail Image
    Some of the metrics are blocked by your 
    consent settings
    Item type:Publication,
    Genetic Background Matters: Population-Based Studies in Model Organisms for Translational Research
    (2022)
    Valeria Olguín
    ;
    Anyelo Durán
    ;
    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