Papandreou Apostolos, 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 Serena, Kriston-Vizi Janos, Gissen Paul, Kurian Manju A, Ketteler Robin
Developmental Neurosciences, Zayed Centre for Research into Rare Disease in Children, University College London Great Ormond Street Institute of Child Health, London, UK.
Laboratory for Molecular Cell Biology, University College London, London, UK.
bioRxiv. 2024 Jun 17:2023.09.13.556416. doi: 10.1101/2023.09.13.556416.
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.
β-螺旋桨蛋白相关神经退行性变（BPAN）是脑铁沉积所致神经退行性变最常见的形式之一，由编码自噬相关蛋白WDR45的基因突变引起。BPAN中自噬、铁过载与神经退行性变之间的联系机制尚不清楚，因此，目前对于这种进行性疾病尚无改善病情的治疗方法。我们建立了一种基于患者诱导多能干细胞（iPSC）的BPAN中脑多巴胺能神经元细胞模型（3例患者、2例年龄匹配的对照和2个同基因对照系），该模型在关键的神经退行性、神经发育和胶原途径中表现出自噬缺陷和异常基因表达。使用美国食品药品监督管理局（FDA）批准的普瑞斯特维克文库进行基于高内涵成像的中通量盲法药物筛选，确定了5种强心苷，它们既能纠正与疾病相关的自噬体形成缺陷，又能恢复BPAN特异性基因表达谱。我们的研究结果具有明确的转化潜力，并强调了基于iPSC的模型在阐明疾病病理生理学和确定早发性单基因疾病的靶向治疗方法方面的实用性。
