Open AccessIsoform-dependent lysosomal degradation and internalization of apolipoprotein E requires autophagy proteins
Author(s) -
Gianna Fote,
Nicolette Geller,
Nikolaos E. Efstathiou,
Nathan Hendricks,
Demetrios G. Vavvas,
Jack C. Reidling,
Leslie Thompson,
Joan S. Steffan
Publication year - 2022
Publication title -
journal of cell science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.384
H-Index - 278
eISSN - 1477-9137
pISSN - 0021-9533
DOI - 10.1242/jcs.258687
Subject(s) - autophagy , internalization , biology , microbiology and biotechnology , lysosome , endosome , apolipoprotein e , gene isoform , cell , intracellular , biochemistry , disease , gene , medicine , enzyme , apoptosis
The human apolipoprotein E4 isoform (APOE4) is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), and lysosomal dysfunction has been implicated in AD pathogenesis. We found, by examining cells stably expressing each APOE isoform, that APOE4 increases lysosomal trafficking, accumulates in enlarged lysosomes and late endosomes, alters autophagic flux and the abundance of autophagy proteins and lipid droplets, and alters the proteomic contents of lysosomes following internalization. We investigated APOE-related lysosomal trafficking further in cell culture, and found that APOE from the post-Golgi compartment is degraded through autophagy. We found that this autophagic process requires the lysosomal membrane protein LAMP2 in immortalized neuron-like and hepatic cells, and in mouse brain tissue. Several macroautophagy-associated proteins were also required for autophagic degradation and internalization of APOE in hepatic cells. The dysregulated autophagic flux and lysosomal trafficking of APOE4 that we observed suggest a possible novel mechanism that might contribute to AD pathogenesis. This article has an associated First Person interview with the first author of the paper.