PICALM Rescues Endocytic Defects Caused by the Alzheimer's Disease Risk Factor APOE4

Priyanka Narayan; Grzegorz Sienski; Julia M. Bonner; Yuan Ta Lin; Jinsoo Seo; Valeriya Baru; Aftabul Haque; Blerta Milo; Leyla A. Akay; Agnese Graziosi; Yelena Freyzon; Dirk Landgraf; William R. Hesse; Julie Valastyan; M. Inmaculada Barrasa; Li Huei Tsai; Susan Lindquist

doi:10.1016/j.celrep.2020.108224

PICALM Rescues Endocytic Defects Caused by the Alzheimer's Disease Risk Factor APOE4

Priyanka Narayan, Grzegorz Sienski, Julia M. Bonner, Yuan Ta Lin, Jinsoo Seo, Valeriya Baru, Aftabul Haque, Blerta Milo, Leyla A. Akay, Agnese Graziosi, Yelena Freyzon, Dirk Landgraf, William R. Hesse, Julie Valastyan, M. Inmaculada Barrasa, Li Huei Tsai, Susan Lindquist

Department of Brain Sciences

Research output: Contribution to journal › Article › peer-review

65 Scopus citations

Abstract

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.

Original language	English
Article number	108224
Journal	Cell Reports
Volume	33
Issue number	1
DOIs	https://doi.org/10.1016/j.celrep.2020.108224
State	Published - 6 Oct 2020

Bibliographical note

Publisher Copyright:
© 2020 The Author(s)

Keywords

Alzheimer's disease
PICALM
apolipoprotein E
astrocytes
endocytosis
genetic risk factors
iPS cells
neurodegenerative disease
stem cells
trafficking
yeast

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2020.108224

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Narayan, P., Sienski, G., Bonner, J. M., Lin, Y. T., Seo, J., Baru, V., Haque, A., Milo, B., Akay, L. A., Graziosi, A., Freyzon, Y., Landgraf, D., Hesse, W. R., Valastyan, J., Barrasa, M. I., Tsai, L. H., & Lindquist, S. (2020). PICALM Rescues Endocytic Defects Caused by the Alzheimer's Disease Risk Factor APOE4. Cell Reports, 33(1), Article 108224. https://doi.org/10.1016/j.celrep.2020.108224

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abstract = "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.",

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author = "Priyanka Narayan and Grzegorz Sienski and Bonner, \{Julia M.\} and Lin, \{Yuan Ta\} and Jinsoo Seo and Valeriya Baru and Aftabul Haque and Blerta Milo and Akay, \{Leyla A.\} and Agnese Graziosi and Yelena Freyzon and Dirk Landgraf and Hesse, \{William R.\} and Julie Valastyan and Barrasa, \{M. Inmaculada\} and Tsai, \{Li Huei\} and Susan Lindquist",

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AU - Narayan, Priyanka

AU - Sienski, Grzegorz

AU - Bonner, Julia M.

AU - Lin, Yuan Ta

AU - Seo, Jinsoo

AU - Baru, Valeriya

AU - Haque, Aftabul

AU - Milo, Blerta

AU - Akay, Leyla A.

AU - Graziosi, Agnese

AU - Freyzon, Yelena

AU - Landgraf, Dirk

AU - Hesse, William R.

AU - Valastyan, Julie

AU - Barrasa, M. Inmaculada

AU - Tsai, Li Huei

AU - Lindquist, Susan

PY - 2020/10/6

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N2 - 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.

AB - 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.

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KW - apolipoprotein E

KW - astrocytes

KW - endocytosis

KW - genetic risk factors

KW - iPS cells

KW - neurodegenerative disease

KW - stem cells

KW - trafficking

KW - yeast

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DO - 10.1016/j.celrep.2020.108224

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ER -

PICALM Rescues Endocytic Defects Caused by the Alzheimer's Disease Risk Factor APOE4

Abstract

Bibliographical note

Keywords

UN SDGs

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