Mutation in Wdr45 leads to early motor dysfunction and widespread aberrant axon terminals in a beta-propeller protein associated neurodegeneration (BPAN) patient-inspired mouse model
Beta-propeller Protein Associated Neurodegeneration (BPAN) is a devastating neurodevelopmental and neurodegenerative disease linked to variants in WDR45. Currently, there is no cure or disease altering treatment for this disease. This is, in part, due to a lack of insight into early phenotypes of BPAN progression and WDR45's role in establishing and maintaining neurological function. Here we generated and characterized a mouse model bearing a c52C>T BPAN patient variant in Wdr45. We show this mutation ablates WDR45 protein expression and alters autophagy in the brain. Behavioral analysis of these mice revealed characteristic signs of BPAN including cognitive impairment, hyperactivity, and motor decline. We show these behaviors coincide with widespread glial activation and development of axonal spheroids in multiple neuron subclasses throughout the brain. Several lines of evidence suggest these spheroids arise from axon terminals. Transcriptomic analysis uncovered multiple disrupted pathways in the cortex including genes associated with synapses, neurites, endosomes, endoplasmic reticulum, and ferroptosis. This is supported by accumulation of the iron regulating transferrin receptor 1 (TFRC) and the endoplasmic reticulum resident calreticulin (CALR) in the cortex as these animals age. CALR forms spheroid structures similar to the axonal spheroids seen in these animals. Taken together, our data suggest that WDR45 is necessary for healthy brain function and maintenance of axon terminals. This model opens the door to therapeutics targeting BPAN and further exploration of the role of WDR45 in neuronal function. Overall design: Cortical samples from 3-month-old Wdr45 c52C>T mice and wildtype mice were collected and RNA was isolated using a TRIzol – Chloroform-Isopropanol protocol. RNA sequencing experiments were then performed with analysis comparing transcriptomes between Wdr45 c52C>T mice and wildtype mice.