期刊
CELL REPORTS
卷 33, 期 1, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.celrep.2020.108224
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资金
- Whitehead Institute for Biomedical Research
- Picower Institute for Learning and Memory
- Robert A. and Renee E. Belfer Family Foundation
- JPB Foundation
- Edward N. and Della L. Thome Foundation
- Howard Hughes Medical Institute
- American Parkinson's Disease Foundation
- NIH [R21 NS087557, NIA RF1AG062377, R01AG058002, U54-HG008097]
- Helen Hay Whitney Foundation
- EMBO fellowship [ALTF 829-2015]
- NIH K99 award [NIA AG055697-03]
- Intramural Research Program of the National Institutes of Health (NIDDK)
- Neurodegeneration Consortium
The epsilon 4 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 counter-parts. 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.
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