Aberrant immunomodulatory signature in β-propeller protein-associated neurodegeneration patient iPSC-derived microglia

This study aimed to identify disease-associated immune and inflammatory transcriptional signatures relevant to BPAN pathogenesis. Microglia are the brain’s resident immune cells, essential for homeostasis and implicated in common neurodegenerative diseases like Alzheimer’s and Parkinson’s disease (PD), where their early activation and sustained inflammatory mediator release precede neuronal loss.

By contrast, their contribution to rare disorders is unclear. β-propeller protein-associated neurodegeneration (BPAN), caused by WDR45 mutations, shares key features with PD, including iron accumulation and dopaminergic neuron loss, but the impact of microglia and mutant WDR45 in BPAN remains unexplored. To address this, we established the first iPSC-derived microglia model from BPAN patients. Integrated transcriptomic and proteomic profiling revealed a shift from a homeostatic to a reactive, pro-inflammatory state with dysregulation of autophagy, and stress response, and chronic immune activation.