Cardiac glycosides restore autophagy flux in an iPSC-derived neuronal model of WDR45 deficiency.
Apostolos PapandreouNivedita SinghLorita GianfrancescoDimitri BudingerKaty BarwickAlexander AgrotisChristin LuftYing ShaoAn-Sofie LenaertsAllison GregorySuh Young JeongPenelope HogarthSusan HayflickSerena BarralJanos Kriston-ViziPaul GissenManju A KurianRobin KettelerPublished in: bioRxiv : the preprint server for biology (2023)
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.
Keyphrases
- early onset
- cell death
- endoplasmic reticulum stress
- gene expression
- signaling pathway
- stem cells
- oxidative stress
- left ventricular
- late onset
- genome wide
- dna methylation
- cerebral ischemia
- high resolution
- copy number
- drug induced
- multiple sclerosis
- diabetic rats
- emergency department
- induced pluripotent stem cells
- white matter
- cell therapy
- high glucose
- resting state
- heart failure
- climate change
- mesenchymal stem cells
- study protocol
- mass spectrometry
- smoking cessation
- amino acid
- blood brain barrier
- photodynamic therapy
- genome wide analysis