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Broken Hearts in Juvenile Dementia: investigating cardiac myocytes in CLN3 disease

Rietdorf, Katja; Coode, Emily; MacDonald, Fraser; Bister, Dirk and Bootman, Martin (2018). Broken Hearts in Juvenile Dementia: investigating cardiac myocytes in CLN3 disease. In: International Meeting of the European Calcium Society, 9-13 Sep 2018, Hamburg, Germany.

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Abstract

CLN3, also called Batten Disease or Juvenile Dementia, is an early onset lysosomal storage disorder. It manifests with blindness at ~8 years of age, followed by seizures and decline of cognitive and motor functions, leading to the patient’s death in the third decade. A co-morbidity of CLN3 is declining cardiac function, including arrhythmias, hypertrophy and echocardiogram abnormalities (Reske-Nielsen E 1981; Michielsen et al. 1984; Tomiyasu et al. 2000; Ostergaard JR 2011; Polychronis Dilaveris 2014). The cardiac dysfunction may result from structural or electrical remodelling of cardiomyocytes. However, although lipopigment accumulation, which is characteristic of CLN3, has been observed in cardiomyocytes, there is limited research into how the heart is altered in CLN3 patients (Reske-Nielsen E 1981; Staropoli et al. 2012).
CLN3 is a lysosomal membrane protein that is implicated Ca2+ signalling and homeostasis. Cells expressing a mutated form of CLN3 that is commonly found in patients (CLN3Δex7/8) show increased sensitivity to thapsigargin-induced autophagy and an increased lysosomal Ca2+ concentration (Chandrachud et al., 2015). Although the sarcoplasmic reticulum is the main Ca2+ store in cardiomyocytes, it has been shown that Ca2+ release from lysosomes via two-pore channels is important for modulation of Ca2+ signals following beta-adrenergic stimulation and the triggering of isoproterenol-induced arrhythmias (Capel et al., 2015, Nebel et al., 2013). The CLN3 protein is therefore expressed within cardiomyocytes in a critical homeostatic/signalling location.
Using iPSC-derived cardiomyocytes from CLN3 patients and healthy donors we are investigating alterations in Ca2+ signalling and structure associated with CLN3 mutation.

Item Type: Conference or Workshop Item
Academic Unit/School: Faculty of Science, Technology, Engineering and Mathematics (STEM) > Life, Health and Chemical Sciences
Faculty of Science, Technology, Engineering and Mathematics (STEM)
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Item ID: 56655
Depositing User: Katja Rietdorf
Date Deposited: 02 Oct 2018 13:45
Last Modified: 07 Dec 2018 11:11
URI: http://oro.open.ac.uk/id/eprint/56655
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