Objective: Beta-propeller protein–associated neurodegeneration (BPAN) is caused by mutations in WDR45 and classified within the neurodegeneration with brain iron accumulation (NBIA) spectrum. Although brain iron deposition is a diagnostic hallmark, the mechanisms initiating neurodegeneration remain unclear. This study aimed to define early pathogenic events in BPAN that are independent of iron accumulation.

Background: BPAN is characterized by early neurodevelopmental impairment followed by parkinsonism and cognitive decline in young adulthood. Neuroimaging studies indicate that iron accumulation does not coincide with symptom onset, suggesting that early disease progression is driven by iron-independent mechanisms. WDR45 encodes the autophagy regulator WIPI4; however, how impaired autophagic flux leads to selective neuronal vulnerability remains poorly understood.

Method: We investigated a Wdr45 knockout mouse model using longitudinal behavioral, histological, and molecular analyses from early postnatal stages through adulthood. Ten mice per group (wild-type [WT] and Wdr45 knockout [KO]) were included in all experiments. Brain-wide calcium accumulation, autophagic flux, and iron distribution were assessed over time.

Results: Wdr45 knockout mice were viable at birth but developed early-onset epilepsy and reduced postnatal survival. Early disease stages showed widespread calcium accumulation and impaired autophagic flux throughout the brain, while iron distribution remained comparable to wild-type mice. Behavioral abnormalities, including emotional dysregulation, social deficits, and cognitive impairment, preceded motor dysfunction. Histological analyses revealed progressive loss of midbrain dopaminergic neurons beginning in early adulthood, followed by secondary iron accumulation.

Conclusion: These findings demonstrate that BPAN pathogenesis is initiated by iron-independent calcium dysregulation and autophagic impairment, with iron accumulation emerging as a downstream consequence of neurodegeneration.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/iron-independent-initiation-of-neurodegeneration-in-bpan/