Phosphatidylinositol-3-phosphate regulates sorting and processing of amyloid precursor protein through the endosomal system

被引：187

作者：

Morel, Etienne ^{[1
,2
]}

Chamoun, Zeina ^{[1
,2
]}

Lasiecka, Zofia M. ^{[1
,2
]}

Chan, Robin B. ^{[1
,2
]}

Williamson, Rebecca L. ^{[1
,2
]}

Vetanovetz, Christopher ^{[1
,2
]}

Dall'Armi, Claudia ^{[1
,2
]}

Simoes, Sabrina ^{[1
,2
]}

Du Jour, Kimberly S. Point ^{[1
,2
]}

McCabe, Brian D. ^{[1
]}

Small, Scott A. ^{[2
,3
]}

Di Paolo, Gilbert ^{[1
,2
]}

机构：

[1] Columbia Univ, Med Ctr, Dept Pathol & Cell Biol, New York, NY 10032 USA

[2] Columbia Univ, Med Ctr, Taub Inst Res Alzheimers Dis & Aging Brain, New York, NY 10032 USA

[3] Columbia Univ, Med Ctr, Dept Neurol, New York, NY 10032 USA

来源：

NATURE COMMUNICATIONS | 2013年 / 4卷

基金：

瑞士国家科学基金会;

关键词：

ALZHEIMERS-DISEASE; CELL-SURFACE; SECRETASE CLEAVAGE; RETROMER COMPLEX; NEURODEGENERATION; INHIBITION; DYSFUNCTION; ENDOCYTOSIS; PATHWAY; DEGRADATION;

D O I：

10.1038/ncomms3250

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：

Defects in endosomal sorting have been implicated in Alzheimer's disease. Endosomal traffic is largely controlled by phosphatidylinositol-3-phosphate, a phosphoinositide synthesized primarily by lipid kinase Vps34. Here we show that phosphatidylinositol-3-phosphate is selectively deficient in brain tissue from humans with Alzheimer's disease and Alzheimer's disease mouse models. Silencing Vps34 causes an enlargement of neuronal endosomes, enhances the amyloidogenic processing of amyloid precursor protein in these organelles and reduces amyloid precursor protein sorting to intraluminal vesicles. This trafficking phenotype is recapitulated by silencing components of the ESCRT (Endosomal Sorting Complex Required for Transport) pathway, including the phosphatidylinositol-3-phosphate effector Hrs and Tsg101. Amyloid precursor protein is ubiquitinated, and interfering with this process by targeted mutagenesis alters sorting of amyloid precursor protein to the intraluminal vesicles of endosomes and enhances amyloid-beta peptide generation. In addition to establishing phosphatidylinositol-3-phosphate deficiency as a contributing factor in Alzheimer's disease, these results clarify the mechanisms of amyloid precursor protein trafficking through the endosomal system in normal and pathological states.

引用

页数：13

共 55 条

[1] Oligomeric amyloid-β peptide disrupts phosphatidylinositol-4,5-bisphosphate metabolism [J].