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https://hdl.handle.net/2440/129461
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Type: | Journal article |
Title: | Retromer regulates the lysosomal clearance of MAPT/tau |
Author: | Carosi, J.M. Hein, L.K. van den Hurk, M. Adams, R. Milky, B. Singh, S. Bardy, C. Denton, D. Kumar, S. Sargeant, T.J. |
Citation: | Autophagy, 2021; 17(9):2217-2237 |
Publisher: | Taylor & Francis |
Issue Date: | 2021 |
ISSN: | 1554-8627 1554-8635 |
Statement of Responsibility: | Julian M. Carosi, Leanne K. Hein, Mark van den Hurk, Robert Adams, Bridget Milky, Sanjna Singh, Cedric Bardy, Donna Denton, Sharad Kumar, and Timothy J. Sargeant |
Abstract: | The macroautophagy/autophagy-lysosome axis enables the clearance and degradation of cytoplasmic components including protein aggregates, damaged organelles and invading pathogens. Protein aggregation and lysosomal system dysfunction in the brain are common features of several late-onset neurological disorders including Alzheimer disease. Spatial overlap between depletion of the endosomal-sorting complex retromer and MAPT/tau aggregation in the brain have been previously reported. However, whether retromer dysfunction plays a direct role in mediating MAPT aggregation remains unclear. Here, we demonstrate that the autophagy-lysosome axis is the primary mode for the clearance of aggregated species of MAPT using both chemical and genetic approaches in cell models of amyloid MAPT aggregation. We show that depletion of the central retromer component VPS35 causes a block in the resolution of autophagy. We establish that this defect underlies marked accumulation of cytoplasmic MAPT aggregates upon VPS35 depletion, and that VPS35 overexpression has the opposite effect. This work illustrates how retromer complex integrity regulates the autophagy-lysosome axis to suppress MAPT aggregation and spread. |
Keywords: | Amyloid; autophagy; lysosome; protein aggregation; tauopathy; VPS35 |
Rights: | © 2020 Informa UK Limited, trading as Taylor & Francis Group |
DOI: | 10.1080/15548627.2020.1821545 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/1124490 http://purl.org/au-research/grants/nhmrc/1103006 |
Published version: | http://dx.doi.org/10.1080/15548627.2020.1821545 |
Appears in Collections: | Aurora harvest 4 Medicine publications |
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