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

John D. Murdoch, Christine M. Rostosky, Sindhuja Gowrisankaran, Amandeep S. Arora, Sandra-Fausia Soukup, Ramon Vidal, Vincenzo Capece, Siona Freytag, Andre Fischer, Patrik Verstreken, Stefan Bonn, Nuno Raimundo, Ira Milosevic
Cell Reports. 2016-10-01; 17(4): 1071-1086
DOI: 10.1016/j.celrep.2016.09.058

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1. Cell Rep. 2016 Oct 18;17(4):1071-1086. doi: 10.1016/j.celrep.2016.09.058. Epub
2016 Oct 6.

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

Murdoch JD(1), Rostosky CM(2), Gowrisankaran S(2), Arora AS(2), Soukup SF(3),
Vidal R(4), Capece V(4), Freytag S(2), Fischer A(5), Verstreken P(3), Bonn S(4),
Raimundo N(6), Milosevic I(7).

Author information:
(1)European Neuroscience Institute (ENI), 37077 Göttingen, Germany; Institute of
Cellular Biochemistry, University Medical Center Göttingen (UMG), 37073
Göttingen, Germany.
(2)European Neuroscience Institute (ENI), 37077 Göttingen, Germany.
(3)VIB Center for Brain & Disease Research, 3000 Leuven, Belgium; KU Leuven
Department of Human Genetics, Leuven Institute for Neurodegenerative Disease
(LIND), 3000 Leuven, Belgium.
(4)Computational Systems Biology, German Center for Neurodegenerative Diseases
(DZNE), 37077 Göttingen, Germany.
(5)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.
(6)Institute of Cellular Biochemistry, University Medical Center Göttingen (UMG),
37073 Göttingen, Germany. Electronic address:
.
(7)European Neuroscience Institute (ENI), 37077 Göttingen, Germany. Electronic
address: .

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.

Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

DOI: 10.1016/j.celrep.2016.09.058
PMCID: PMC5080600
PMID: 27720640 [Indexed for MEDLINE]


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