Endophilin-A Deficiency Induces the Foxo3a-Fbxo32 Network in the Brain and Causes Dysregulation of Autophagy and the Ubiquitin-Proteasome System.

Endophilin-A, a well-characterized endocytic adaptor essential for synaptic vesicle recycling, has recently been linked to neurodegeneration. We report here that endophilin-A deficiency results in impaired movement, age-dependent ataxia, and neurodegeneration in mice. Transcriptional analysis of endophilin-A mutant mice, complemented by proteomics, highlighted ataxia- and protein-homeostasis-related genes and revealed upregulation of ...
the E3-ubiquitin ligase FBXO32/atrogin-1 and its transcription factor FOXO3A. FBXO32 overexpression triggers apoptosis in cultured cells and neurons but, remarkably, coexpression of endophilin-A rescues it. FBXO32 interacts with all three endophilin-A proteins. Similarly to endophilin-A, FBXO32 tubulates membranes and localizes on clathrin-coated structures. Additionally, FBXO32 and endophilin-A are necessary for autophagosome formation, and both colocalize transiently with autophagosomes. Our results point to a role for endophilin-A proteins in autophagy and protein degradation, processes that are impaired in their absence, potentially contributing to neurodegeneration and ataxia.
Mesh Terms:
Acyltransferases, Aging, Animals, Apoptosis, Ataxia, Autophagosomes, Autophagy, Brain, Forkhead Box Protein O3, HeLa Cells, Hippocampus, Homeostasis, Humans, Male, Mice, Mice, Knockout, Movement Disorders, Muscle Proteins, Mutation, Nerve Degeneration, Parkinson Disease, Proteasome Endopeptidase Complex, Protein Binding, SKP Cullin F-Box Protein Ligases, Transcription, Genetic, Ubiquitin, Up-Regulation
Cell Rep
Date: Dec. 18, 2015
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