Journal Article

DZNE-2026-00636

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Aberrant immunomodulatory signature in β-propeller protein-associated neurodegeneration patient iPSC-derived microglia.

Özata, G.Extern* ; Wise, R.Extern* ; Cardona-Alberich, A. ; Mayeen, N. F. ; Müller, S. A.DZNE* ; Lichtenthaler, S. F.DZNE* ; Zecca, L. ; Burbulla, L. F. (Last author)DZNE*

2026
Springer Nature [London]

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Please use a persistent id in citations: doi:10.1038/s41598-026-55648-w

Abstract: 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 contribute to neuronal loss. However, their role in 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 pathophysiology remains unexplored. To address this, we established the first induced pluripotent stem stell (iPSC)-derived microglia model from BPAN patients. Parallel targeted transcriptomic and secretomic profiling revealed a shift from a homeostatic microglial toward a stress-adapted and transcriptionally reprogrammed state characterized by selective remodeling of immune signaling pathways and dysregulation of autophagy and cellular stress responses. Complementary secretomic analysis identified reduced secretion of lysosomal enzymes alongside increased shedding of immune-associated surface proteins, indicating altered lysosomal trafficking and remodeling of microglial immune signaling. These findings identify a distinct microglial phenotype in BPAN and implicate microglial dysfunction as a potential contributor to disease mechanisms, highlighting new avenues for therapeutic strategies targeting neuroimmune pathways.

Keyword(s): Humans (MeSH) ; Microglia: metabolism (MeSH) ; Microglia: immunology (MeSH) ; Microglia: pathology (MeSH) ; Induced Pluripotent Stem Cells: metabolism (MeSH) ; Induced Pluripotent Stem Cells: cytology (MeSH) ; Neurodegenerative Diseases: genetics (MeSH) ; Neurodegenerative Diseases: immunology (MeSH) ; Neurodegenerative Diseases: pathology (MeSH) ; Neurodegenerative Diseases: metabolism (MeSH) ; Carrier Proteins: genetics (MeSH) ; Carrier Proteins: metabolism (MeSH) ; Lysosomes: metabolism (MeSH) ; Mutation (MeSH) ; WDR45 protein, human ; Carrier Proteins

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Contributing Institute(s):

1. Translational Disease Modeling (AG Burbulla)
2. Neuroproteomics (AG Lichtenthaler)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

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