Wdfy3-dependent autophagy impairment recapitulates presymptomatic neurodegenerative signatures in mice

Abstract

Abstract WDFY3/ALFY is an adaptor protein involved in selective autophagy. Loss of Wdfy3 in mice causes severe deficits in neuronal health, and pathogenic mutations in WDFY3 are associated with neurodevelopmental disorders in humans. As impaired autophagy is increasingly implicated in Parkinson’s disease (PD) and other neurodegenerative disorders, we investigated whether Wdfy3 haploinsufficiency produces early molecular and cellular signatures of neurodegeneration in Wdfy3 +/lacZ mice, given that these diseases often exhibit presymptomatic alterations preceding overt clinical manifestations. Cortical tissue from 3-month-old presymptomatic mice showed significant proteomic overlap with both patient-derived PD cell lines and human brain proteomic datasets, particularly from the substantia nigra, underscoring the translational relevance of this model. Consistent with disease progression, immunofluorescence analyses of the cortex and substantia nigra from 14-month-old mice revealed significant dysregulation of multiple markers associated with neurodegeneration. Together, these findings demonstrate that impaired autophagy resulting from reduced Wdfy3 expression recapitulates key features of neurodegenerative disease at both early and later stages. By providing a platform to investigate presymptomatic pathogenic mechanisms, this model may inform the development and testing of future diagnostic and therapeutic strategies aimed at preserving neuronal health.