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

John D. Murdoch | Zendy; Christine M. Rostosky | Zendy; Sindhuja Gowrisankaran | Zendy; Amandeep Singh Arora | Zendy; SandraFausia Soukup | Zendy; Ramón Vidal | Zendy; Vincenzo Capece | Zendy; Siona Freytag | Zendy; André Fischer | Zendy; Patrik Verstreken | Zendy; Stefan Bonn | Zendy; Nuno Raimundo | Zendy; Ira Milošević | Zendy

Open Access

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

Author(s) -

John D. Murdoch,

Christine M. Rostosky,

Sindhuja Gowrisankaran,

Amandeep Singh Arora,

SandraFausia Soukup,

Ramón Vidal,

Vincenzo Capece,

Siona Freytag,

André Fischer,

Patrik Verstreken,

Stefan Bonn,

Nuno Raimundo,

Ira Milošević

Publication year - 2016

Publication title -

cell reports

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 6.264

H-Index - 154

eISSN - 2639-1856

pISSN - 2211-1247

DOI - 10.1016/j.celrep.2016.09.058

Subject(s) - neurodegeneration , microbiology and biotechnology , autophagy , ubiquitin , endocytic cycle , signal transducing adaptor protein , parkin , retromer , mitophagy , ubiquitin ligase , biology , chemistry , endocytosis , endosome , signal transduction , parkinson's disease , gene , biochemistry , intracellular , apoptosis , receptor , medicine , disease

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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