Characterizing Histologic Brain Defects in a Mouse Model of the Rare Neurodegenerative Disorder BPAN — 44p — Prithvi Patthi, Brandon Meyerink; Krishna Karia, Dr. Louis-Jan Pilaz

β-Propeller Protein Associated Neurodegeneration (BPAN) is a rare neurodegenerative disorder caused by mutations in the WDR45 gene. This disorder is characterized by a biphasic mode of progression, with seizures and developmental delays followed by parkinsonism and dystonia. The histological, cellular, and molecular defects linking WDR45 mutations to BPAN remain largely unclear. In this study, I used a BPAN mouse model inspired by a patient mutation to characterize the histological brain defects, promoting our understanding of BPAN’s pathophysiology. First, I examined whether WDR45 loss triggers axonal death in the Basal Ganglia in 12-month-old mouse models. Next, I evaluated the quantity and distribution of Parvalbumin positive (PARV+) neurons and protein aggregates in the somatosensory cortex (SSC) using immunofluorescence. Furthermore, I tested whether PARV+ aggregates are present in the presynaptic compartment by performing immunohistochemistry using the marker Synaptophysin. Then, I investigated the glial response surrounding PARV+ aggregates in the Deep Cerebellar Nuclei (DCN) by performing immunofluorescence using antibodies against IBA 1 and GFAP, which mark activated microglia and astrocytes, respectively. Finally, I performed a longitudinal analysis to examine possible changes in glial response in 3-, 6-, 9-, and 12-month mouse models using immunohistochemistry. Results show no significant difference in the projection densities between the BPAN samples and control samples. Additionally, there was no significant difference in the quantity and distribution of PARV+ cell bodies between KO and WT mouse models. However, PARV+ aggregates’
distribution did not match that of PARV+ cell bodies, suggesting that PARV+ cell aggregates locate in the presynaptic compartments of those cells, which was confirmed by co-immunofluorescence with the Synaptophysin marker. These findings provide valuable insights into BPAN’s pathophysiology, contributing to a better understanding of the disorder and potentially guiding future therapeutic strategies. These insights could be relevant for more common neurodegenerative disorders, such as Alzheimer’s and Parkinson’s diseases.

Sanford Health
Dr. Louis-Jan Pilaz