PICALM Rescues Endocytic Defects Caused by the Alzheimer’s Disease Risk Factor APOE4
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...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | English |
| Published: |
Elsevier BV
2021
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| Online Access: | https://hdl.handle.net/1721.1/134090 |
| _version_ | 1826199185470259200 |
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| author | Narayan, Priyanka Sienski, Grzegorz Bonner, Julia M Lin, Yuan-Ta Seo, Jinsoo Baru, Valeriya Haque, Aftabul Milo, Blerta Akay, Leyla A Graziosi, Agnese Freyzon, Yelena Landgraf, Dirk Hesse, William R Valastyan, Julie Barrasa, M Inmaculada Tsai, Li-Huei Lindquist, Susan |
| author2 | Whitehead Institute for Biomedical Research |
| author_facet | Whitehead Institute for Biomedical Research Narayan, Priyanka Sienski, Grzegorz Bonner, Julia M Lin, Yuan-Ta Seo, Jinsoo Baru, Valeriya Haque, Aftabul Milo, Blerta Akay, Leyla A Graziosi, Agnese Freyzon, Yelena Landgraf, Dirk Hesse, William R Valastyan, Julie Barrasa, M Inmaculada Tsai, Li-Huei Lindquist, Susan |
| author_sort | Narayan, Priyanka |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T11:16:05Z |
| format | Article |
| id | mit-1721.1/134090 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T11:16:05Z |
| publishDate | 2021 |
| publisher | Elsevier BV |
| record_format | dspace |
| spelling | mit-1721.1/1340902023-09-07T21:02:43Z PICALM Rescues Endocytic Defects Caused by the Alzheimer’s Disease Risk Factor APOE4 Narayan, Priyanka Sienski, Grzegorz Bonner, Julia M Lin, Yuan-Ta Seo, Jinsoo Baru, Valeriya Haque, Aftabul Milo, Blerta Akay, Leyla A Graziosi, Agnese Freyzon, Yelena Landgraf, Dirk Hesse, William R Valastyan, Julie Barrasa, M Inmaculada Tsai, Li-Huei Lindquist, Susan Whitehead Institute for Biomedical Research Picower Institute for Learning and Memory Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Massachusetts Institute of Technology. Department of Biology Howard Hughes Medical Institute 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. 2021-10-27T19:58:03Z 2021-10-27T19:58:03Z 2020 2021-03-19T15:15:56Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/134090 en 10.1016/J.CELREP.2020.108224 Cell Reports Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier BV Elsevier |
| spellingShingle | Narayan, Priyanka Sienski, Grzegorz Bonner, Julia M Lin, Yuan-Ta Seo, Jinsoo Baru, Valeriya Haque, Aftabul Milo, Blerta Akay, Leyla A Graziosi, Agnese Freyzon, Yelena Landgraf, Dirk Hesse, William R Valastyan, Julie Barrasa, M Inmaculada Tsai, Li-Huei Lindquist, Susan PICALM Rescues Endocytic Defects Caused by the Alzheimer’s Disease Risk Factor APOE4 |
| title | PICALM Rescues Endocytic Defects Caused by the Alzheimer’s Disease Risk Factor APOE4 |
| title_full | PICALM Rescues Endocytic Defects Caused by the Alzheimer’s Disease Risk Factor APOE4 |
| title_fullStr | PICALM Rescues Endocytic Defects Caused by the Alzheimer’s Disease Risk Factor APOE4 |
| title_full_unstemmed | PICALM Rescues Endocytic Defects Caused by the Alzheimer’s Disease Risk Factor APOE4 |
| title_short | PICALM Rescues Endocytic Defects Caused by the Alzheimer’s Disease Risk Factor APOE4 |
| title_sort | picalm rescues endocytic defects caused by the alzheimer s disease risk factor apoe4 |
| url | https://hdl.handle.net/1721.1/134090 |
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