Modeling endophilin-mediated A β disposal in glioma cells

Publication date: Available online 4 July 2018 Source:Biochimica et Biophysica Acta (BBA) - Molecular Cell Research Author(s): Bing Sun, Ping Fan, Meijian Liao, Yaou Zhang Autophagy dysregulation has emerged in age-related neurological diseases (Ulland et al.; Matheoud et al.; Ashkenazi et al. [1–3]). Alzheimer Disease (AD), the most common progressive neurodegenerative disorder, is characterized by the accumulation of amyloid-β (Aβ) plaques caused by aberrant Aβ metabolism (Qiang et al.; Sevigny et al.; Ittner et al. [4–6]). Glia constitute the brain immune system and ingest extracellular Aβ for degradation via the autophagy-lysosome machinery (Ries and Sastre; Cho et al. [7, 8]). Here, we model the molecular rationale for this clearance process in glioma cells by showing that miR34a inhibits autophagy-mediated disposal of Aβ fibrils and identifying two novel direct targets of miR34a, endophilin-3 and cathepsin B (CTSB, a previously reported enzyme for Aβ degrading (Sun et al. [9])). 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 Aβ while small interfering RNA (siRNA)-mediated endophilin-3 knockdown slowed down Aβ clearance and blocked autolysosome formation. Mechanistically, gene ontology (GO) analysis of the endophilin-3 interactome identified by mass spectrometry uncovered enriched components involved in a...
Source: Biochimica et Biophysica Acta (BBA) Molecular Cell Research - Category: Molecular Biology Source Type: research