Wdfy3-dependent autophagy impairment recapitulates presymptomatic neurodegenerative signatures in mice
Aldo Vorkapich1, Arshi Mustafa2,3, Amanda L Flores-Torres1
1Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, Davis, CA, 95616, USA.
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.
Insights
Reduced WDFY3 protein levels in mice mimic early Parkinson's disease (PD) molecular changes. This model reveals how impaired autophagy contributes to neurodegeneration, aiding future diagnostic and therapeutic development for PD.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- WDFY3/ALFY is an adaptor protein crucial for selective autophagy.
- Loss of WDFY3 function in mice and humans is linked to neuronal deficits and neurodevelopmental disorders.
- Impaired autophagy is a known factor in Parkinson's disease (PD) and other neurodegenerative conditions.
Purpose of the Study:
- To investigate if WDFY3 haploinsufficiency in mice (Wdfy3+/lacZ) recapitulates early molecular and cellular signs of neurodegeneration.
- To establish a preclinical model for studying presymptomatic neurodegenerative mechanisms.
Main Methods:
- Proteomic analysis of cortical tissue from presymptomatic 3-month-old Wdfy3+/lacZ mice.
- Comparison of mouse proteomic data with human PD cell lines and substantia nigra datasets.
- Immunofluorescence analysis of cortical and substantia nigra tissues from 14-month-old mice to assess neurodegeneration markers.
Main Results:
- Proteomic data from presymptomatic mice showed significant overlap with human PD patient data, especially from the substantia nigra.
- Immunofluorescence revealed dysregulation of key neurodegeneration markers in older mice, consistent with disease progression.
- Reduced WDFY3 expression models key features of neurodegenerative disease across different stages.
Conclusions:
- WDFY3 haploinsufficiency in mice provides a relevant model for studying early-stage neurodegeneration.
- This model can help elucidate presymptomatic pathogenic mechanisms in neurodegenerative diseases.
- The findings support the development of novel diagnostic and therapeutic strategies for preserving neuronal health in conditions like PD.
