Cardiac glycosides restore autophagy flux in an iPSC-derived neuronal model of WDR45 deficiency

Papandreou, A.; Singh, N.; Gianfrancesco, L.; Budinger, D.; Barwick, K.; Agrotis, A.; Luft, C.; Shao, Y.; Lenaerts, A.-S.; Gregory, A.; Jeong, S. Y.; Hogarth, P.; Hayflick, S.; Barral, S.; Kriston-Vizi, J.; Gissen, P.; Kurian, M. A. A.; Ketteler, R.

doi:10.1101/2023.09.13.556416

bioRxiv · 10.1101/2023.09.13.556416

Cardiac glycosides restore autophagy flux in an iPSC-derived neuronal model of WDR45 deficiency

Papandreou, A.·Singh, N.·Gianfrancesco, L.·Budinger, D.·Barwick, K.·Agrotis, A.·Luft, C.·Shao, Y.·Lenaerts, A.-S.·Gregory, A.·Jeong, S. Y.·Hogarth, P.·Hayflick, S.·Barral, S.·Kriston-Vizi, J.·Gissen, P.·Kurian, M. A. A.·Ketteler, R.

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Abstract

Beta-Propeller Protein-Associated Neurodegeneration (BPAN) is one of the commonest forms of Neurodegeneration with Brain Iron Accumulation, caused by mutations in the gene encoding the autophagy-related protein, WDR45. The mechanisms linking autophagy, iron overload and neurodegeneration in BPAN are poorly understood and, as a result, there are currently no disease-modifying treatments for this progressive disorder. We have developed a patient-derived, induced pluripotent stem cell (iPSC)-based midbrain dopaminergic neuronal cell model of BPAN (3 patient, 2 age-matched controls and 2 isogenic control lines) which shows defective autophagy and aberrant gene expression in key neurodegenerative, neurodevelopmental and collagen pathways. A high content imaging-based medium-throughput blinded drug screen using the FDA-approved Prestwick library identified 5 cardiac glycosides that both corrected disease-related defective autophagosome formation and restored BPAN-specific gene expression profiles. Our findings have clear translational potential and emphasise the utility of iPSC-based modelling in elucidating disease pathophysiology and identifying targeted therapeutics for early-onset monogenic disorders.

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Papandreou, A., Singh, N., Gianfrancesco, L., Budinger, D., Barwick, K., Agrotis, A., Luft, C., Shao, Y., Lenaerts, A.-S., Gregory, A., Jeong, S. Y., Hogarth, P., Hayflick, S., Barral, S., Kriston-Vizi, J., Gissen, P., Kurian, M. A. A., Ketteler, R.. 2023-09-13. Cardiac glycosides restore autophagy flux in an iPSC-derived neuronal model of WDR45 deficiency. https://doi.org/10.1101/2023.09.13.556416

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