A dwdr45 knock-out drosophila model to decipher the role of autophagy in BPAN

Dec 29, 2025Human molecular genetics

Using a fruit fly model without the dwdr45 gene to study how cell recycling affects BPAN

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Abstract

Drosophila flies with a knockout of the WDR45 gene exhibit BPAN-like phenotypes and a shortened lifespan.

Impaired locomotor function and seizure-like behavior are observed in flies lacking the dWDR45 gene.
Dysregulation of autophagy and iron imbalances are present in the dwdr45 knockout flies.
Inducing autophagy in these flies improves lifespan and seizure-like behavior, but does not restore locomotor function.
These findings suggest that defective autophagy may contribute to some, but not all, BPAN-related phenotypes.

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Beta-propeller protein-associated neurodegeneration (BPAN) is a rare neurological disorder characterized by severe cognitive and motor impairments. BPAN is caused by de novo pathogenic variants in the WDR45 gene on the X chromosome. WDR45 gene encodes the protein WDR45/WIPI4, a known regulator of autophagy. A defective autophagy has been observed in cellular models of BPAN disease and is associated with neurological dysfunctions in wdr45 knockout (KO) mice. However, it remains unclear whether the autophagic defect directly contributes to all WDR45 loss-induced phenotypes or whether other WDR45-dependent cellular functions are involved. To investigate this, we generated a CRISPR/Cas9-mediated KO of CG11975 (dwdr45 KO), the Drosophila homolog of WDR45. Our analysis revealed that dwdr45 KO flies display BPAN-like phenotypes, including impaired locomotor function, seizure-like behavior, autophagy dysregulation and iron dyshomeostasis. Additionally, dwdr45 KO flies exhibit shortened lifespan compared to control flies. These findings demonstrate that dwdr45 KO fly is a relevant in-vivo model for investigating the key cellular and molecular mechanisms underlying BPAN-associated phenotypes. Here we showed that induction of autophagy in dwdr45 KO flies improved both the shortened lifespan and the seizure-like behavior, but did not restore locomotor function. This suggests that defective autophagy contributes to some, but not all, aspects of the phenotypes resulting from loss of dWdr45 function.

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A dwdr45 knock-out drosophila model to decipher the role of autophagy in BPAN

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