Functional links between Aβ toxicity, endocytic trafficking, and Alzheimer's disease risk factors in yeast.
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.
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
Sebastian
S
Treusch
Shusei
S
Hamamichi
Jessica L
JL
Goodman
Kent E S
KE
Matlack
Chee Yeun
CY
Chung
Valeriya
V
Baru
Joshua M
JM
Shulman
Antonio
A
Parrado
Brooke J
BJ
Bevis
Julie S
JS
Valastyan
Haesun
H
Han
Malin
M
Lindhagen-Persson
Eric M
EM
Reiman
Denis A
DA
Evans
David A
DA
Bennett
Anders
A
Olofsson
Philip L
PL
DeJager
Rudolph E
RE
Tanzi
Kim A
KA
Caldwell
Guy A
GA
Caldwell
Susan
S
Lindquist
D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000166:cytology / Q000235:genetics / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D002966:Clathrin / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D004198:Disease Susceptibility; D004705:Endocytosis; D056726:Genetic Association Studies; D005820:Genetic Testing; D005971:Glutamates / Q000378:metabolism; D006801:Humans; D034041:Monomeric Clathrin Assembly Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000502:physiology; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D055503:Protein Multimerization; D021381:Protein Transport; D051381:Rats; D012307:Risk Factors; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D055571:Secretory Pathway
D016229:Amyloid beta-Peptides; D002966:Clathrin; D005971:Glutamates; D034041:Monomeric Clathrin Assembly Proteins; C439003:PICALM protein, human; D010446:Peptide Fragments; D029701:Saccharomyces cerevisiae Proteins; C075222:amyloid beta-protein (1-42)