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

Abstract

SummaryEndophilin-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.

Retrograde transport of TrkB-containing autophagosomes via the adaptor AP-2 mediates neuronal complexity and prevents neurodegeneration

“…A role of AP-2 in neuronal branching is supported by data from mammalian neurons and from Drosophila suggesting a key role for AP-2-associated kinase 1, a crucial activator of AP-2, in dendrite arborization54. Interestingly, recent data have identified an endocytosis-independent role for the endocytic protein endophilin in neuronal autophagosome formation5556, for example, upstream of the function of AP-2 in autophagosome transport described in this study. How AP-2 switches between its functions in endocytosis and retrograde transport of TrkB-containing autophagosomes remains to be determined.…”

Malfunctions in synaptic membrane trafficking in early pathology of Parkinson’s disease: New molecular clues

“…It is altered in the cortex of PD patients, and it interacts with two hallmark PD proteins, the E3 ubiquitin ligase parkin and the leucine-rich repeat kinase LRRK2, the most commonly disrupted gene in familial PD (Murdoch et al, 2016;Soukup et al, 2016;Soukup and Verstreken, 2017). Unbiased proteomic screening of brain proteins in mice lacking all three synuclein genes revealed a prominent increase in endophilin 1 levels (Burre et al, 2013).…”

“…Mouse endophilin triple knockout (TKO) has a distinct morphological and cellular phenotype characterized by impaired SV recycling, diminished autophagy/altered protein homeostasis, increased apoptosis and gliosis, neurodegeneration, motor impairments and reduced lifespan. A partial loss of endophilin in mice also results in neurodegeneration, ataxia and early lethality (Milosevic et al, 2011;Cao, Milosevic, Giovedi and De Camilli, 2014;Murdoch et al, 2016).…”

“…Several recent studies linked endophilin and its endocytic binding partner synaptojanin to the maturation of autophagosomes in the synapse (Murdoch et al, 2016;Soukup et al, 2016;Soukup and Verstreken, 2017), which expanded its role far beyond the SV recycling and synaptic compartment, and allowed linking it to pathological neurodegenerative conditions, including PD, in accordance with the complex phenotype of the endophilin TKO (Fig. 1).…”

“…1). Endophilin 1 localizes on autophagosomal membranes and is critical for the maturation of synaptic autophagosomes (Murdoch et al, 2016;Soukup et al, 2016).…”