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

Author:

Papandreou ApostolosORCID,Singh Nivedita,Gianfrancesco Lorita,Budinger Dimitri,Barwick Katy,Agrotis Alexander,Luft Christin,Shao Ying,Lenaerts An-Sofie,Gregory Allison,Jeong Suh Young,Hogarth Penelope,Hayflick Susan,Barral SerenaORCID,Kriston-Vizi Janos,Gissen PaulORCID,Kurian Manju A,Ketteler Robin

Abstract

AbstractBeta-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.

Publisher

Cold Spring Harbor Laboratory

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