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Updated: Oct 31, 2025
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Wdfy3 regulates glycophagy, mitophagy, and synaptic plasticity
Eleonora Napoli1, Alexios A Panoutsopoulos2,3, Patricia Kysar4
1Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA, USA.
Summary
Wdfy3 protein deficiency impairs cellular recycling, leading to mitochondrial and glycogen buildup in the brain. This impacts synaptic function and may contribute to neurodevelopmental disorders.
Area of Science:
- Cell Biology
- Neuroscience
- Biochemistry
Background:
- Autophagy is a crucial cellular process for recycling components and maintaining quality control.
- Wdfy3 (WD repeat domain 3) is a macroautophagy scaffold protein implicated in neurodevelopmental disorders.
- Previous work linked Wdfy3 to mitophagy, a specific form of autophagy targeting mitochondria.
Purpose of the Study:
- To confirm Wdfy3 haploinsufficiency effects on mitophagy.
- To investigate Wdfy3's broader role in brain bioenergetics and synaptic plasticity.
- To explore Wdfy3's impact on glycogen metabolism and degradation.
Main Methods:
- Utilized a mouse model of Wdfy3 haploinsufficiency.
- Assessed mitophagy, mitochondrial morphology, and synaptic density.
- Analyzed glycogen particle elimination, synthesis, and degradation pathways.
Main Results:
- Wdfy3 deficiency decreased mitophagy and led to mitochondrial accumulation and altered morphology.
- Reduced mitochondrial localization at synapses and decreased synaptic density were observed.
- Defective glycogen particle elimination and a shift towards glycogen synthesis were noted, causing age-dependent brain glycogen deposits and cerebellar hypoplasia.
Conclusions:
- Wdfy3 plays a significant role in maintaining brain bioenergetics and synaptic plasticity.
- Wdfy3 influences both mitochondrial quality control and glycogen metabolism via macroautophagy.
- Dysregulation of Wdfy3 impacts neuronal structure and function, potentially contributing to neurodevelopmental deficits.
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