Endophilin-A Deficiency Induces the Foxo3a-Fbxo32 Network in the Brain and Causes Dysregulation of Autophagy and the Ubiquitin-Proteasome System
2016 | journal article
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Endophilin-A Deficiency Induces the Foxo3a-Fbxo32 Network in the Brain and Causes Dysregulation of Autophagy and the Ubiquitin-Proteasome System
Murdoch, J. ; Rostosky, C. ; Gowrisankaran, S.; Arora, A. ; Soukup, S.-F.; Vidal, R. & Capece, V. et al. (2016)
Cell Reports, 17(4) pp. 1071-1086. DOI: https://doi.org/10.1016/j.celrep.2016.09.058
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Details
- Authors
- Murdoch, John D. ; Rostosky, Christine M. ; Gowrisankaran, Sindhuja; Arora, Amandeep S. ; Soukup, Sandra-Fausia; Vidal, Ramon ; Capece, Vincenzo ; Freytag, Siona; Fischer, Andre ; Verstreken, Patrik; Bonn, Stefan ; Raimundo, Nuno ; Milosevic, Ira
- 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.
- Issue Date
- 2016
- Journal
- Cell Reports
- ISSN
- 2211-1247
- Language
- English
- Sponsor
- Open-Access-Publikationsfonds 2016