Functional Links Between Aβ Toxicity, Endocytic Trafficking, and Alzheimer's Disease Risk Factors in Yeast

被引：278

作者：

Treusch, Sebastian ^{[1
,2
]}

Hamamichi, Shusei ^{[1
,3
]}

Goodman, Jessica L. ^{[1
]}

Matlack, Kent E. S. ^{[1
,2
]}

Chung, Chee Yeun ^{[1
]}

Baru, Valeriya ^{[1
,2
]}

Shulman, Joshua M. ^{[4
,5
,7
]}

Parrado, Antonio ^{[8
]}

Bevis, Brooke J. ^{[1
]}

Valastyan, Julie S. ^{[1
,2
,6
]}

Han, Haesun ^{[1
]}

Lindhagen-Persson, Malin ^{[9
]}

Reiman, Eric M. ^{[10
,11
,12
,13
]}

Evans, Denis A. ^{[14
]}

Bennett, David A. ^{[15
]}

Olofsson, Anders ^{[9
]}

DeJager, Philip L. ^{[4
,5
,6
,7
]}

Tanzi, Rudolph E. ^{[8
]}

Caldwell, Kim A. ^{[3
]}

Caldwell, Guy A. ^{[3
]}

Lindquist, Susan ^{[1
,2
]}

机构：

[1] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA

[2] MIT, Howard Hughes Med Inst, Dept Biol, Cambridge, MA 02139 USA

[3] Univ Alabama, Dept Biol Sci, Tuscaloosa, AL 35487 USA

[4] Brigham & Womens Hosp, Inst Neurosci, Program Translat NeuroPsychiat Genom, Dept Neurol, Boston, MA 02115 USA

[5] Brigham & Womens Hosp, Inst Neurosci, Program Translat NeuroPsychiat Genom, Dept Psychiat, Boston, MA 02115 USA

[6] Harvard Univ, Sch Med, Boston, MA 02115 USA

[7] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA

[8] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Genet & Aging Res Unit, Charlestown, MA 02129 USA

[9] Umea Univ, Dept Med Biochem & Biophys, S-90187 Umea, Sweden

[10] Translat Genom Res Inst, Neurogenom Div, Phoenix, AZ 85004 USA

[11] Arizona Alzheimers Consortium, Phoenix, AZ 85004 USA

[12] Univ Arizona, Banner Alzheimers Inst, Phoenix, AZ 85006 USA

[13] Univ Arizona, Dept Psychiat, Phoenix, AZ 85006 USA

[14] Rush Univ, Med Ctr, Dept Internal Med, Rush Inst Hlth Aging, Chicago, IL 60612 USA

[15] Rush Univ, Med Ctr, Dept Neurol Sci, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA

来源：

SCIENCE | 2011年 / 334卷 / 6060期

关键词：

GENOME-WIDE ASSOCIATION; ALPHA-SYNUCLEIN; SACCHAROMYCES-CEREVISIAE; ENDOPLASMIC-RETICULUM; IDENTIFIES VARIANTS; COMMON VARIANTS; PEPTIDE; OLIGOMERS; MEMBRANE; CELLS;

D O I：

10.1126/science.1213210

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

A beta (beta-amyloid peptide) is an important contributor to Alzheimer's disease (AD). We modeled A beta 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 A beta was previously unknown. The factors identified in yeast modified A beta toxicity in glutamatergic neurons of Caenorhabditis elegans and in primary rat cortical neurons. In yeast, A beta impaired the endocytic trafficking of a plasma membrane receptor, which was ameliorated by endocytic pathway factors identified in the yeast screen. Thus, links between A beta, endocytosis, and human AD risk factors can be ascertained with yeast as a model system.

引用

页码：1241 / 1245

页数：5

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