TY - JOUR
T1 - Endophilin-A Deficiency Induces the Foxo3a-Fbxo32 Network in the Brain and Causes Dysregulation of Autophagy and the Ubiquitin-Proteasome System
AU - Murdoch, John D.
AU - Rostosky, Christine M.
AU - Gowrisankaran, Sindhuja
AU - Arora, Amandeep S.
AU - Soukup, Sandra Fausia
AU - Vidal, Ramon
AU - Capece, Vincenzo
AU - Freytag, Siona
AU - Fischer, Andre
AU - Verstreken, Patrik
AU - Bonn, Stefan
AU - Raimundo, Nuno
AU - Milosevic, Ira
N1 - Funding Information:
We thank M. König, E. Rizou, J. Liebig, and S. Burkhardt for superb technical assistance; A. Cepeda for help with protein expression and purification; B. Flix for cloning; and J. Kroll for video processing. This work was supported in part by grants from Schram-Stiftung T287/25457 and Deutsche Forschungsgemeinschaft (DFG) (Emmy Noether Young Investigator Award MI 1702/1 and SFB889/2/A08) to I.M., ERC Starting Grant 337327 to N.R., an Alexander von Humboldt postdoctoral fellowship to J.D.M., and a SySy fellowship to S.G.
Publisher Copyright:
© 2016 The Author(s)
PY - 2016/10/18
Y1 - 2016/10/18
N2 - 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.
AB - 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.
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U2 - 10.1016/j.celrep.2016.09.058
DO - 10.1016/j.celrep.2016.09.058
M3 - Article
C2 - 27720640
AN - SCOPUS:84992049086
SN - 2211-1247
VL - 17
SP - 1071
EP - 1086
JO - Cell Reports
JF - Cell Reports
IS - 4
ER -