Crosstalk of protein clearance, inflammasome, and Ca2+ channels in retinal pigment epithelium derived from age-related macular degeneration patients

Viivi Karema-Jokinen, Ali Koskela, Maria Hytti, Heidi Hongisto, Taina Viheriälä, Mikko Liukkonen, Tommi Torsti, Heli Skottman, Anu Kauppinen, Soile Nymark, Kai Kaarniranta

    Tutkimustuotos: ArtikkeliScientificvertaisarvioitu

    3 Lataukset (Pure)

    Abstrakti

    Degeneration and/or dysfunction of retinal pigment epithelium (RPE) is generally detected as the formation of intracellular and extracellular protein aggregates, called lipofuscin and drusen, respectively, in patients with age-related macular degeneration (AMD), the leading cause of blindness in the elderly population. These clinical hallmarks are linked to dysfunctional protein homeostasis and inflammation and furthermore, are both regulated by changes in intracellular Ca2+ concentration. While many other cellular mechanisms have been considered in the investigations of AMD-RPE, there has been relatively little work on understanding the interactions of protein clearance, inflammation, and Ca2+ dynamics in disease pathogenesis. Here we established induced pluripotent stem cell–derived RPE from two patients with advanced AMD and from an age- and gender-matched control subject. We studied autophagy and inflammasome activation under disturbed proteostasis in these cell lines and investigated changes in their intracellular Ca2+ concentration and L-type voltage-gated Ca2+ channels. Our work demonstrated dysregulated autophagy and inflammasome activation in AMD-RPE accompanied by reduced intracellular free Ca2+ levels. Interestingly, we found currents through L-type voltage-gated Ca2+ channels to be diminished and showed these channels to be significantly localized to intracellular compartments in AMD-RPE. Taken together, the alterations in Ca2+ dynamics in AMD-RPE together with dysregulated autophagy and inflammasome activation indicate an important role for Ca2+ signaling in AMD pathogenesis, providing new avenues for the development of therapeutic approaches.

    AlkuperäiskieliEnglanti
    Artikkeli104770
    Sivumäärä17
    JulkaisuJournal of Biological Chemistry
    Vuosikerta299
    Numero6
    DOI - pysyväislinkit
    TilaJulkaistu - kesäk. 2023
    OKM-julkaisutyyppiA1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä

    Julkaisufoorumi-taso

    • Jufo-taso 2

    !!ASJC Scopus subject areas

    • Biochemistry
    • Molecular Biology
    • Cell Biology

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