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

• Published in: Cell reports (Cambridge) Vol. 17; no. 4; pp. 1071 - 1086
• Main 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18.10.2016; Cell Press; Elsevier
• Subjects: Acyltransferases - deficiency; Acyltransferases - metabolism; Aging - pathology; Animals; Apoptosis; ataxia; Ataxia - genetics; Ataxia - pathology; Autophagosomes - metabolism; Autophagy; Brain - metabolism; endocytosis; endophilin; FBXO32; Forkhead Box Protein O3 - genetics; Forkhead Box Protein O3 - metabolism; HeLa Cells; Hippocampus - metabolism; Hippocampus - pathology; Homeostasis - genetics; Humans; Male; Mice; Mice, Knockout; Movement Disorders - complications; Movement Disorders - pathology; Muscle Proteins - genetics; Muscle Proteins - metabolism; Mutation - genetics; Nerve Degeneration - complications; Nerve Degeneration - pathology; neurodegeneration; next-generation sequencing; Parkinson Disease - genetics; Parkinson Disease - pathology; Parkinson’s disease; Proteasome Endopeptidase Complex - metabolism; Protein Binding; protein homeostasis; SKP Cullin F-Box Protein Ligases - genetics; SKP Cullin F-Box Protein Ligases - metabolism; Transcription, Genetic; Ubiquitin - metabolism; ubiquitin-proteasome system; Up-Regulation; endophilin; ubiquitin-proteasome system; autophagy; ataxia; next-generation sequencing; protein homeostasis; neurodegeneration; endocytosis; FBXO32; Parkinson’s disease
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.09.058

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. [Display omitted] •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.