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PMID: 22033521 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Functional links between Aβ toxicity, endocytic trafficking, and Alzheimer's disease risk factors in yeast.

Science (New York, N.Y.) ·Vol. 334 ·No. 6060 ·2011-12-02 ·Pages 1241-5

Treusch S, Hamamichi S, Goodman JL, Matlack KE, Chung CY, Baru V, Shulman JM, Parrado A, Bevis BJ, Valastyan JS, Han H, Lindhagen-Persson M, Reiman EM, Evans DA, Bennett DA, Olofsson A, DeJager PL, Tanzi RE, Caldwell KA, Caldwell GA, Lindquist S

Abstract

Aβ (beta-amyloid peptide) is an important contributor to Alzheimer's disease (AD). We modeled Aβ toxicity in yeast by directing the peptide to the secretory pathway. A genome-wide screen for toxicity modifiers identified the yeast homolog of phosphatidylinositol binding clathrin assembly protein (PICALM) and other endocytic factors connected to AD whose relationship to Aβ was previously unknown. The factors identified in yeast modified Aβ toxicity in glutamatergic neurons of Caenorhabditis elegans and in primary rat cortical neurons. In yeast, Aβ impaired the endocytic trafficking of a plasma membrane receptor, which was ameliorated by endocytic pathway factors identified in the yeast screen. Thus, links between Aβ, endocytosis, and human AD risk factors can be ascertained with yeast as a model system.

MeSH Terms
Alzheimer Disease/genetics,metabolism Amyloid beta-Peptides/chemistry,genetics,metabolism Animals Animals, Genetically Modified Caenorhabditis elegans/cytology,genetics,metabolism Cell Membrane/metabolism Cells, Cultured Clathrin/metabolism Cytoskeleton/metabolism Disease Susceptibility Endocytosis Genetic Association Studies Genetic Testing Glutamates/metabolism Humans Monomeric Clathrin Assembly Proteins/genetics,metabolism Neurons/physiology Peptide Fragments/chemistry,genetics,metabolism Protein Multimerization Protein Transport Rats Risk Factors Saccharomyces cerevisiae/cytology,genetics,growth & development,metabolism Saccharomyces cerevisiae Proteins/genetics,metabolism Secretory Pathway
Chemicals
Amyloid beta-Peptides Clathrin Glutamates Monomeric Clathrin Assembly Proteins PICALM protein, human Peptide Fragments Saccharomyces cerevisiae Proteins amyloid beta-protein (1-42)
Authors & Affiliations
21 authors, click to expand affiliations / ORCID
Treusch Sebastian
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
Hamamichi Shusei
Goodman Jessica L
Matlack Kent E S
Chung Chee Yeun
Baru Valeriya
Shulman Joshua M
Parrado Antonio
Bevis Brooke J
Valastyan Julie S
Han Haesun
Lindhagen-Persson Malin
Reiman Eric M
Evans Denis A
Bennett David A
Olofsson Anders
DeJager Philip L
Tanzi Rudolph E
Caldwell Kim A
Caldwell Guy A
Lindquist Susan
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Article Info
Journal
Science (New York, N.Y.)
Abbr.
Science
ISSN
1095-9203
DOI
10.1126/science.1213210
Published
2011-12-02
Epub
2011-00-27
Pages
1241-5
Language
English
Region
United States
NLM ID
0404511
PMCID
PMC3281757
Subset
IM
Grants
NIA NIH HHS · K08AG034290 · United States
NINDS NIH HHS · F32 NS067782-02 · United States
NINDS NIH HHS · F32 NS067782 · United States
NIA NIH HHS · K08 AG034290 · United States
NIA NIH HHS · P30 AG010161 · United States
Howard Hughes Medical Institute · United States
NIA NIH HHS · R01AG15819 · United States
NIA NIH HHS · P30AG10161 · United States
NIA NIH HHS · P30 AG019610 · United States
NIA NIH HHS · R01 AG015819 · United States
NIA NIH HHS · R01 AG017917 · United States
NIA NIH HHS · R01AG17917 · United States
Corrections
CommentIn
PMID: 22144604
External Links
PubMed source DOI: 10.1126/science.1213210 PMC Full Text View journal details
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