Endophilin-A Deficiency Induces the Foxo3a-Fbxo32 Network in the Brain and Causes Dysregulation of Autophagy and the Ubiquitin-Proteasome System
Murdoch, John D. ; Rostosky, Christine M. ; Gowrisankaran, Sindhuja ; Arora, Amandeep S. ; Soukup, Sandra-Fausia ; Vidal, Ramon ; Capece, Vincenzo ; Freytag, Siona et al.
Zitierfähiger Link (URL): http://resolver.sub.uni-goettingen.de/purl?gs-1/13844
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.
Gefördert von der EU
Projekt: Mitochondria, Peroxisomes and Lysosomes - the ""menage a trois"" of cellular metabolism (MITOPEXLYSONETWORK)