title: Endophilin-A Deficiency Induces the Foxo3a-Fbxo32 Network in the Brain and Causes Dysregulation of Autophagy and the Ubiquitin-Proteasome System.
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.
authors.affiliation: European Neuroscience Institute (ENI), 37077 Göttingen, Germany; Institute of Cellular Biochemistry, University Medical Center Göttingen (UMG), 37073 Göttingen, Germany.
authors.forename: John D
authors.initials: JD
authors.lastname: Murdoch
authors.affiliation: European Neuroscience Institute (ENI), 37077 Göttingen, Germany.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Rostosky
authors.affiliation: European Neuroscience Institute (ENI), 37077 Göttingen, Germany.
authors.forename: Sindhuja
authors.initials: S
authors.lastname: Gowrisankaran
authors.affiliation: European Neuroscience Institute (ENI), 37077 Göttingen, Germany.
authors.forename: Amandeep S
authors.initials: AS
authors.lastname: Arora
authors.affiliation: VIB Center for Brain & Disease Research, 3000 Leuven, Belgium; KU Leuven Department of Human Genetics, Leuven Institute for Neurodegenerative Disease (LIND), 3000 Leuven, Belgium.
authors.forename: Sandra-Fausia
authors.initials: SF
authors.lastname: Soukup
authors.affiliation: Computational Systems Biology, German Center for Neurodegenerative Diseases (DZNE), 37077 Göttingen, Germany.
authors.forename: Ramon
authors.initials: R
authors.lastname: Vidal
authors.affiliation: Computational Systems Biology, German Center for Neurodegenerative Diseases (DZNE), 37077 Göttingen, Germany.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Capece
authors.affiliation: European Neuroscience Institute (ENI), 37077 Göttingen, Germany.
authors.forename: Siona
authors.initials: S
authors.lastname: Freytag
authors.affiliation: Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), 37077 Göttingen, Germany; Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, 37077 Göttingen, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Fischer
authors.affiliation: VIB Center for Brain & Disease Research, 3000 Leuven, Belgium; KU Leuven Department of Human Genetics, Leuven Institute for Neurodegenerative Disease (LIND), 3000 Leuven, Belgium.
authors.forename: Patrik
authors.initials: P
authors.lastname: Verstreken
authors.affiliation: Computational Systems Biology, German Center for Neurodegenerative Diseases (DZNE), 37077 Göttingen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Bonn
authors.affiliation: Institute of Cellular Biochemistry, University Medical Center Göttingen (UMG), 37073 Göttingen, Germany. Electronic address: nuno.raimundo@med.uni-goettingen.de.
authors.forename: Nuno
authors.initials: N
authors.lastname: Raimundo
authors.affiliation: European Neuroscience Institute (ENI), 37077 Göttingen, Germany. Electronic address: imilose@gwdg.de.
authors.forename: Ira
authors.initials: I
authors.lastname: Milosevic
mesh_terms: D000217:Acyltransferases / Q000172:deficiency* / Q000378:metabolism; D000375:Aging / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D001259:Ataxia / Q000235:genetics / Q000473:pathology; D000071182:Autophagosomes / Q000378:metabolism; D001343:Autophagy; D001921:Brain / Q000378:metabolism*; D000071316:Forkhead Box Protein O3 / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009069:Movement Disorders / Q000150:complications / Q000473:pathology; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000150:complications / Q000473:pathology; D010300:Parkinson Disease / Q000235:genetics / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011485:Protein Binding; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D025801:Ubiquitin / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D000071316:Forkhead Box Protein O3; C474033:FoxO3 protein, mouse; D009124:Muscle Proteins; D025801:Ubiquitin; D000217:Acyltransferases; C018764:2-acylglycerophosphate acyltransferase; C440907:FBXO32 protein, human; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; D046988:Proteasome Endopeptidase Complex
keywords: FBXO32; Parkinson’s disease; ataxia; autophagy; endocytosis; endophilin; neurodegeneration; next-generation sequencing; protein homeostasis; ubiquitin-proteasome system