PICALM Rescues Endocytic Defects Caused by the Alzheimer’s Disease Risk Factor APOE4
| Autor: | Julia Maeve Bonner, Susan Lindquist, Leyla Anne Akay, M. Inmaculada Barrasa, Julie S. Valastyan, Agnese Graziosi, Valeriya Baru, Aftabul Haque, Yelena Freyzon, Grzegorz Sienski, William R. Hesse, Li-Huei Tsai, Priyanka Narayan, Yuan-Ta Lin, Jinsoo Seo, Blerta Milo, Dirk Landgraf |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Apolipoprotein E Endocytic cycle Apolipoprotein E4 Biology Endocytosis General Biochemistry Genetics and Molecular Biology Article PICALM 03 medical and health sciences 0302 clinical medicine Alzheimer Disease Risk Factors trafficking mental disorders genetic risk factors Humans endocytosis Allele Induced pluripotent stem cell lcsh:QH301-705.5 apolipoprotein E Signal transducing adaptor protein Alzheimer's disease Cell biology 030104 developmental biology lcsh:Biology (General) lipids (amino acids peptides and proteins) Stem cell human activities 030217 neurology & neurosurgery |
| Zdroj: | Cell Reports, Vol 33, Iss 1, Pp 108224-(2020) Cell Rep Elsevier |
| ISSN: | 2211-1247 |
| Popis: | Summary: The ε4 allele of apolipoprotein E (APOE4) is a genetic risk factor for many diseases, including late-onset Alzheimer’s disease (AD). We investigate the cellular consequences of APOE4 in human iPSC-derived astrocytes, observing an endocytic defect in APOE4 astrocytes compared with their isogenic APOE3 counterparts. Given the evolutionarily conserved nature of endocytosis, we built a yeast model to identify genetic modifiers of the endocytic defect associated with APOE4. In yeast, only the expression of APOE4 results in dose-dependent defects in both endocytosis and growth. We discover that increasing expression of the early endocytic adaptor protein Yap1802p, a homolog of the human AD risk factor PICALM, rescues the APOE4-induced endocytic defect. In iPSC-derived human astrocytes, increasing expression of PICALM similarly reverses endocytic disruptions. Our work identifies a functional interaction between two AD genetic risk factors—APOE4 and PICALM—centered on the conserved biological process of endocytosis. |
| Databáze: | OpenAIRE |
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