Anatomy and Neuroscience - Research Publications

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Author: Elliott, David × Author: Parker, Benjamin × Author: Watt, Kevin × End date: 2023 × Start date: 2021 ×

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    GLA-modified RNA treatment lowers GB3 levels in iPSC-derived cardiomyocytes from Fabry-affected individuals
    Huurne, MT ; Parker, BL ; Liu, NQ ; Qian, EL ; Vivien, C ; Karavendzas, K ; Mills, RJ ; Saville, JT ; Abu-Bonsrah, D ; Wise, AF ; Hudson, JE ; Talbot, AS ; Finn, PF ; Martini, PGV ; Fuller, M ; Ricardo, SD ; Watt, KI ; Nicholls, KM ; Porrello, ER ; Elliott, DA (Cell Press, 2023-09-07)
    Recent studies in non-human model systems have shown therapeutic potential of nucleoside-modified messenger RNA (modRNA) treatments for lysosomal storage diseases. Here, we assessed the efficacy of a modRNA treatment to restore the expression of the galactosidase alpha (GLA), which codes for α-Galactosidase A (α-GAL) enzyme, in a human cardiac model generated from induced pluripotent stem cells (iPSCs) derived from two individuals with Fabry disease. Consistent with the clinical phenotype, cardiomyocytes from iPSCs derived from Fabry-affected individuals showed accumulation of the glycosphingolipid Globotriaosylceramide (GB3), which is an α-galactosidase substrate. Furthermore, the Fabry cardiomyocytes displayed significant upregulation of lysosomal-associated proteins. Upon GLA modRNA treatment, a subset of lysosomal proteins were partially restored to wild-type levels, implying the rescue of the molecular phenotype associated with the Fabry genotype. Importantly, a significant reduction of GB3 levels was observed in GLA modRNA-treated cardiomyocytes, demonstrating that α-GAL enzymatic activity was restored. Together, our results validate the utility of iPSC-derived cardiomyocytes from affected individuals as a model to study disease processes in Fabry disease and the therapeutic potential of GLA modRNA treatment to reduce GB3 accumulation in the heart.
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    Alpha kinase 3 signaling at the M-band maintains sarcomere integrity and proteostasis in striated muscle
    McNamara, JW ; Parker, BL ; Voges, HK ; Mehdiabadi, NR ; Bolk, F ; Ahmad, F ; Chung, JD ; Charitakis, N ; Molendijk, J ; Zech, ATL ; Lal, S ; Ramialison, M ; Karavendzas, K ; Pointer, HL ; Syrris, P ; Lopes, LR ; Elliott, PM ; Lynch, GS ; Mills, RJ ; Hudson, JE ; Watt, KI ; Porrello, ER ; Elliott, DA (SPRINGERNATURE, 2023-02)
    Abstract Muscle contraction is driven by the molecular machinery of the sarcomere. As phosphorylation is a critical regulator of muscle function, the identification of regulatory kinases is important for understanding sarcomere biology. Pathogenic variants in alpha kinase 3 (ALPK3) cause cardiomyopathy and musculoskeletal disease, but little is known about this atypical kinase. Here we show that ALPK3 is an essential component of the M-band of the sarcomere and define the ALPK3-dependent phosphoproteome. ALPK3 deficiency impaired contractility both in human cardiac organoids and in the hearts of mice harboring a pathogenic truncating Alpk3 variant. ALPK3-dependent phosphopeptides were enriched for sarcomeric components of the M-band and the ubiquitin-binding protein sequestosome-1 (SQSTM1) (also known as p62). Analysis of the ALPK3 interactome confirmed binding to M-band proteins including SQSTM1. In human pluripotent stem cell-derived cardiomyocytes modeling cardiomyopathic ALPK3 mutations, sarcomeric organization and M-band localization of SQSTM1 were abnormal suggesting that this mechanism may underly disease pathogenesis.