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

Cell Reports (Oct 2020)

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

Affiliations

Priyanka Narayan: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Genetics and Biochemistry Branch, NIDDK, National Institutes of Health, Bethesda, MD 20814, USA
Grzegorz Sienski: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
Julia M. Bonner: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Yuan-Ta Lin: Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Jinsoo Seo: Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Valeriya Baru: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
Aftabul Haque: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
Blerta Milo: Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Leyla A. Akay: Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Agnese Graziosi: Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Yelena Freyzon: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
Dirk Landgraf: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
William R. Hesse: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
Julie Valastyan: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
M. Inmaculada Barrasa: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
Li-Huei Tsai: Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Corresponding author
Susan Lindquist: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Cambridge, MA 02139, USA

Journal volume & issue: Vol. 33, no. 1
p. 108224

Abstract

Read online

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.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

About the journal

Abstract

Keywords