Mechanistic Insights into Iron Accumulation in WDR45 Mutant Neurons Linked to β-propeller-Associated Neurodegeneration

Broad Objectives: This proposal investigates new pathways underlying BPAN (β-propellerassociated neurodegeneration) progression using patient-derived dopamine (DA) neurons. Background and Rationale: Iron is essential for key biological processes including oxygen transport and mitochondrial respiration. Neurodegeneration with brain iron accumulation (NBIA) are a group of diseases which include BPAN, a disease caused by mutant WDR45 (WD repeat domain 45) leading to DA neuropathology. Thus, while WDR45 has been implicated in autophagy, how mutant WD45 causes iron accumulation and neurodegeneration remains unclear.