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A dwdr45 knock-out drosophila model to decipher the role of autophagy in BPAN.
Hum Mol Genet.
Beta-propeller protein-associated neurodegeneration (BPAN) is a rare neurologicaldisorder characterized by severe cognitive and motor impairments. BPAN is causedby de novo pathogenic variants in the WDR45 gene on the X chromosome. WDR45 geneencodes the protein WDR45/WIPI4, a known regulator of autophagy. A defectiveautophagy has been observed in cellular models of BPAN disease and is associatedwith neurological dysfunctions in wdr45 knockout (KO) mice. However, it remainsunclear whether the autophagic defect directly contributes to all WDR45loss-induced phenotypes or whether other WDR45-dependent cellular functions areinvolved. To investigate this, we generated a CRISPR/Cas9-mediated KO of CG11975(dwdr45 KO), the Drosophila homolog of WDR45. Our analysis revealed that dwdr45KO 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 controlflies. These findings demonstrate that dwdr45 KO fly is a relevant in-vivo modelfor investigating the key cellular and molecular mechanisms underlyingBPAN-associated phenotypes. Here we showed that induction of autophagy in dwdr45KO flies improved both the shortened lifespan and the seizure-like behavior, butdid not restore locomotor function. This suggests that defective autophagycontributes to some, but not all, aspects of the phenotypes resulting from lossof dWdr45 function.
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