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.
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Acknowledgements
Data used in the preparation of this article were obtained on 2025-10-26 from the Parkinson’s Progression Markers Initiative (PPMI) database (https://www.ppmi-info.org/access-dataspecimens/download-data), RRID: SCR_006431. For up-to-date information on the study, visitwww.ppmi-info.org.PPMI—a public-private partnership—is funded by the Michael J. Fox Foundation for Parkinson’sResearch, and funding partners; including 4D Pharma, AbbVie, AcureX, Allergan, Amathus Therapeutics, Aligning Science Across Parkinson’s (ASAP), AskBio, Avid Radiopharmaceuticals, BIAL, BioArctic, Biogen, Biohaven, BioLegend, BlueRock Therapeutics, Bristol Myers Squibb, Calico Labs, Capsida Biotherapeutics, Celgene, Cerevel Therapeutics, Coave Therapeutics, DaCapo Brainscience, Denali, Edmond J. Safra Foundation, Eli Lilly, Gain Therapeutics, GE Healthcare, Genentech, GSK, Golub Capital, Handl Therapeutics, Insitro, Jazz Pharmaceuticals, Johnson & Johnson Innovative Medicine, Lundbeck, Merck, Meso Scale Discovery, Mission Therapeutics, Neurocrine Biosciences, Neuron23, Neuropore, Pfizer, Piramal, Prevail Therapeutics, Roche, Sanofi, Servier, Sun Pharma Advanced Research Company, Takeda, Teva, UCB, Vanqua Bio, Verily, Voyager Therapeutics, The Weston Family Foundation, Yumanity Therapeutics.
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The study was supported by NIH NS128751 (CG), discretionary funds (CG), and NIH MH115347 (KSZ).
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All listed authors made substantial contributions to the following: (i) the conception and design of the study, the acquisition of data, or the analysis and interpretation of data; (ii) drafting the article or critically revising its important intellectual content; (iii) final approval of the version submitted. A.V. prepared figures, performed data analysis, wrote, edited, and reviewed the text; A. L. F-T. performed most of the experimental work, wrote, edited, and reviewed the text; A.M. performed tissue collection, histology, immunofluorescent analysis, and imaging. K.S.Z. contributed to colony maintenance and tissue collections, writing, review, and editing, supervision; C.G. conceptualization, proteomics, methodology, supervising, formal analysis, writing original draft, preparing figures; writing-review & editing. All authors have agreed on the final version of this study.
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Vorkapich, A., Mustafa, A., Flores-Torres, A.L. et al. Wdfy3-dependent autophagy impairment recapitulates presymptomatic neurodegenerative signatures in mice. Sci Rep (2026). https://doi.org/10.1038/s41598-026-43314-0
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DOI: https://doi.org/10.1038/s41598-026-43314-0
