Endophilin-A Deficiency Induces the Foxo3a-Fbxo32 Network in the Brain and Causes Dysregulation of Autophagy and the Ubiquitin-Proteasome System
| Autor: | 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 |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Male
Aging genetics [SKP Cullin F-Box Protein Ligases] Transcription Genetic Muscle Proteins Apoptosis metabolism [Hippocampus] genetics [Muscle Proteins] Hippocampus pathology [Ataxia] metabolism [Forkhead Box Protein O3] genetics [Homeostasis] Mice pathology [Aging] genetics [Parkinson Disease] metabolism [Ubiquitin] complications [Movement Disorders] Fbxo32 protein mouse Homeostasis lcsh:QH301-705.5 Mice Knockout protein homeostasis Movement Disorders Forkhead Box Protein O3 neurodegeneration Brain pathology [Nerve Degeneration] Parkinson Disease genetics [Ataxia] metabolism [Autophagosomes] Up-Regulation metabolism [Acyltransferases] Protein Binding Proteasome Endopeptidase Complex autophagy metabolism [Muscle Proteins] FBXO32 protein human genetics [Mutation] Article FBXO32 endophilin Autophagy deficiency [Acyltransferases] Animals Humans endocytosis FoxO3 protein mouse ddc:610 metabolism [Proteasome Endopeptidase Complex] SKP Cullin F-Box Protein Ligases Endophilin-A Ubiquitin-Proteasome System Ubiquitin ataxia Autophagosomes metabolism [SKP Cullin F-Box Protein Ligases] pathology [Movement Disorders] pathology [Parkinson Disease] complications [Nerve Degeneration] pathology [Hippocampus] lcsh:Biology (General) metabolism [Brain] Mutation Nerve Degeneration Parkinson’s disease genetics [Forkhead Box Protein O3] 2-acylglycerophosphate acyltransferase next-generation sequencing ubiquitin-proteasome system Acyltransferases HeLa Cells |
| Zdroj: | Cell Reports, Vol 17, Iss 4, Pp 1071-1086 (2016) Cell reports 17(4), 1071-1086 (2016). doi:10.1016/j.celrep.2016.09.058 Cell Reports |
| DOI: | 10.1016/j.celrep.2016.09.058 |
| Popis: | Summary 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. Graphical Abstract Highlights • Endophilin-A is needed for autophagosome formation in mammalian neurons and brain • Absence of endophilin-A upregulates the E3-ubiquitin ligase FBXO32 • FBXO32-endophilin-A interaction maintains neuronal health and protein homeostasis • Endophilin-A KO mice show age-dependent ataxia, motor impairments, and neurodegeneration Regulation of protein homeostasis and autophagy has become a promising line of research in the neurodegeneration field. Murdoch et al. now find that endophilin-A, a key factor in clathrin-mediated endocytosis, regulates protein homeostasis through the Foxo3a-Fbxo32 network. |
| Databáze: | OpenAIRE |
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