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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: NCL 2018, 12-16 Sep 2018, London. UK.

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Abstract

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).

The CLN3 protein 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 twopore 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 location that is critical for Ca2+ homeostasis/ signalling.

Using iPSC-derived cardiomyocytes from CLN3 patients and healthy donors we are investigating putative alterations in cellular functions associated with CLN3 mutation. Specifically, calcium signalling measurements, autophagy assays, and lysosomal measurement tools are being developed to assess phenotypic changes caused by CLN3 mutation.

Item Type: Conference or Workshop Item
Copyright Holders: 2018 The Authors
Academic Unit/School: Faculty of Science, Technology, Engineering and Mathematics (STEM) > Life, Health and Chemical Sciences
Faculty of Science, Technology, Engineering and Mathematics (STEM)
Item ID: 56656
Depositing User: Katja Rietdorf
Date Deposited: 08 Oct 2018 09:12
Last Modified: 07 Dec 2018 11:11
URI: http://oro.open.ac.uk/id/eprint/56656
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