| First Author | Sun B | Year | 2018 |
| Journal | Biochim Biophys Acta Mol Cell Res | Volume | 1865 |
| Issue | 10 | Pages | 1385-1396 |
| PubMed ID | 30049645 | Mgi Jnum | J:268323 |
| Mgi Id | MGI:6267527 | Doi | 10.1016/j.bbamcr.2018.06.015 |
| Citation | Sun B, et al. (2018) Modeling endophilin-mediated Abeta disposal in glioma cells. Biochim Biophys Acta Mol Cell Res 1865(10):1385-1396 |
| abstractText | Autophagy dysregulation has emerged in age-related neurological diseases (Ulland et al.; Matheoud et al.; Ashkenazi et al.). Alzheimer Disease (AD), the most common progressive neurodegenerative disorder, is characterized by the accumulation of amyloid-beta (Abeta) plaques caused by aberrant Abeta metabolism (Qiang et al.; Sevigny et al.; Ittner et al.). Glia constitute the brain immune system and ingest extracellular Abeta for degradation via the autophagy-lysosome machinery (Ries and Sastre; Cho et al.). Here, we model the molecular rationale for this clearance process in glioma cells by showing that miR34a inhibits autophagy-mediated disposal of Abeta fibrils and identifying two novel direct targets of miR34a, endophilin-3 and cathepsin B (CTSB, a previously reported enzyme for Abeta degrading (Sun et al.)). Bioinformatics analyses revealed that endophilin-3 expresses at a significantly lower level in neurodegenerative diseases. Its gain-of-function substantially promotes both uptake and degradation of Abeta while small interfering RNA (siRNA)-mediated endophilin-3 knockdown slowed down Abeta clearance and blocked autolysosome formation. Mechanistically, gene ontology (GO) analysis of the endophilin-3 interactome identified by mass spectrometry uncovered enriched components involved in actin binding (with the highest score). Importantly, we validated that the actin-binding protein phostensin interacted with endophilin-3. Phostensin knockdown restored endophilin-3-mediated up-regulation of Abeta clearance. Thus, our findings indicate that miR34a inhibits Abeta clearance by targeting endophilin-3 and CTSB at multiple steps including uptake and autophagy-mediated degradation. |
