1. Endophilin-A Deficiency Induces the Foxo3a-Fbxo32 Network in the Brain and Causes Dysregulation of Autophagy and the Ubiquitin-Proteasome System.
- Author
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Murdoch JD, Rostosky CM, Gowrisankaran S, Arora AS, Soukup SF, Vidal R, Capece V, Freytag S, Fischer A, Verstreken P, Bonn S, Raimundo N, and Milosevic I
- Subjects
- Acyltransferases metabolism, Aging pathology, Animals, Apoptosis, Ataxia genetics, Ataxia pathology, Autophagosomes metabolism, Forkhead Box Protein O3 genetics, HeLa Cells, Hippocampus metabolism, Hippocampus pathology, Homeostasis genetics, Humans, Male, Mice, Mice, Knockout, Movement Disorders complications, Movement Disorders pathology, Muscle Proteins genetics, Mutation genetics, Nerve Degeneration complications, Nerve Degeneration pathology, Parkinson Disease genetics, Parkinson Disease pathology, Protein Binding, SKP Cullin F-Box Protein Ligases genetics, Transcription, Genetic, Up-Regulation, Acyltransferases deficiency, Autophagy, Brain metabolism, Forkhead Box Protein O3 metabolism, Muscle Proteins metabolism, Proteasome Endopeptidase Complex metabolism, SKP Cullin F-Box Protein Ligases metabolism, Ubiquitin metabolism
- Abstract
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., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
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