A genome wide analysis of ubiquitin ligases in APP processing identifies a novel regulator of BACE1 mRNA levels

Amy S. Espeseth; Qian Huang; Adam Gates; Min Xu; Yuanjiang Yu; Adam J. Simon; Xiao Ping Shi; Xiaohua Zhang; Paul Hodor; David J. Stone; Julja Burchard; Guy Cavet; Steven Bartz; Peter Linsley; William J. Ray; Daria Hazuda

doi:10.1016/j.mcn.2006.07.003

A genome wide analysis of ubiquitin ligases in APP processing identifies a novel regulator of BACE1 mRNA levels

Amy S. Espeseth, Qian Huang, Adam Gates, Min Xu, Yuanjiang Yu, Adam J. Simon, Xiao Ping Shi, Xiaohua Zhang, Paul Hodor, David J. Stone, Julja Burchard, Guy Cavet, Steven Bartz, Peter Linsley, William J. Ray, Daria Hazuda

Biostatistics

Research output: Contribution to journal › Article › peer-review

24 Scopus citations

Abstract

Proteolysis of β-amyloid precursor protein (APP) into amyloid β peptide (Aβ) by β- and γ-secretases is a critical step in the pathogenesis of Alzheimer's Disease (AD), but the pathways regulating secretases are not fully characterized. Ubiquitinylation, which is dysregulated in AD, may affect APP processing. Here, we describe a screen for APP processing modulators using an siRNA library targeting 532 predicted ubiquitin ligases. Seven siRNA pools diminished Aβ production. Of these, siRNAs targeting PPIL2 (hCyp-60) suppressed β-site cleavage. Knockdown of PPIL2 mRNA decreased BACE1 mRNA, while overexpression of PPIL2 cDNA enhanced BACE1 mRNA levels. Microarray analysis of PPIL2 or BACE1 knockdown indicated that genes affected by BACE1 knockdown are a subset of those dependent upon PPIL2; suggesting that BACE1 expression is downstream of PPIL2. The association of PPIL2 with BACE expression and its requirement for Aβ production suggests new approaches to discover disease modifying agents for AD.

Original language	English
Pages (from-to)	227-235
Number of pages	9
Journal	Molecular and Cellular Neuroscience
Volume	33
Issue number	3
DOIs	https://doi.org/10.1016/j.mcn.2006.07.003
State	Published - Nov 6 2006

Keywords

Alzheimer's
BACE1 regulation
PPIL2
hCyp-60
siRNA screen

ASJC Scopus subject areas

Molecular Biology
Cellular and Molecular Neuroscience
Cell Biology

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10.1016/j.mcn.2006.07.003

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Espeseth, A. S., Huang, Q., Gates, A., Xu, M., Yu, Y., Simon, A. J., Shi, X. P., Zhang, X., Hodor, P., Stone, D. J., Burchard, J., Cavet, G., Bartz, S., Linsley, P., Ray, W. J., & Hazuda, D. (2006). A genome wide analysis of ubiquitin ligases in APP processing identifies a novel regulator of BACE1 mRNA levels. Molecular and Cellular Neuroscience, 33(3), 227-235. https://doi.org/10.1016/j.mcn.2006.07.003

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title = "A genome wide analysis of ubiquitin ligases in APP processing identifies a novel regulator of BACE1 mRNA levels",

abstract = "Proteolysis of β-amyloid precursor protein (APP) into amyloid β peptide (Aβ) by β- and γ-secretases is a critical step in the pathogenesis of Alzheimer's Disease (AD), but the pathways regulating secretases are not fully characterized. Ubiquitinylation, which is dysregulated in AD, may affect APP processing. Here, we describe a screen for APP processing modulators using an siRNA library targeting 532 predicted ubiquitin ligases. Seven siRNA pools diminished Aβ production. Of these, siRNAs targeting PPIL2 (hCyp-60) suppressed β-site cleavage. Knockdown of PPIL2 mRNA decreased BACE1 mRNA, while overexpression of PPIL2 cDNA enhanced BACE1 mRNA levels. Microarray analysis of PPIL2 or BACE1 knockdown indicated that genes affected by BACE1 knockdown are a subset of those dependent upon PPIL2; suggesting that BACE1 expression is downstream of PPIL2. The association of PPIL2 with BACE expression and its requirement for Aβ production suggests new approaches to discover disease modifying agents for AD.",

keywords = "Alzheimer's, BACE1 regulation, PPIL2, hCyp-60, siRNA screen",

author = "Espeseth, {Amy S.} and Qian Huang and Adam Gates and Min Xu and Yuanjiang Yu and Simon, {Adam J.} and Shi, {Xiao Ping} and Xiaohua Zhang and Paul Hodor and Stone, {David J.} and Julja Burchard and Guy Cavet and Steven Bartz and Peter Linsley and Ray, {William J.} and Daria Hazuda",

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Espeseth, AS, Huang, Q, Gates, A, Xu, M, Yu, Y, Simon, AJ, Shi, XP, Zhang, X, Hodor, P, Stone, DJ, Burchard, J, Cavet, G, Bartz, S, Linsley, P, Ray, WJ & Hazuda, D 2006, 'A genome wide analysis of ubiquitin ligases in APP processing identifies a novel regulator of BACE1 mRNA levels', Molecular and Cellular Neuroscience, vol. 33, no. 3, pp. 227-235. https://doi.org/10.1016/j.mcn.2006.07.003

TY - JOUR

T1 - A genome wide analysis of ubiquitin ligases in APP processing identifies a novel regulator of BACE1 mRNA levels

AU - Espeseth, Amy S.

AU - Huang, Qian

AU - Gates, Adam

AU - Xu, Min

AU - Yu, Yuanjiang

AU - Simon, Adam J.

AU - Shi, Xiao Ping

AU - Zhang, Xiaohua

AU - Hodor, Paul

AU - Stone, David J.

AU - Burchard, Julja

AU - Cavet, Guy

AU - Bartz, Steven

AU - Linsley, Peter

AU - Ray, William J.

AU - Hazuda, Daria

PY - 2006/11/6

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N2 - Proteolysis of β-amyloid precursor protein (APP) into amyloid β peptide (Aβ) by β- and γ-secretases is a critical step in the pathogenesis of Alzheimer's Disease (AD), but the pathways regulating secretases are not fully characterized. Ubiquitinylation, which is dysregulated in AD, may affect APP processing. Here, we describe a screen for APP processing modulators using an siRNA library targeting 532 predicted ubiquitin ligases. Seven siRNA pools diminished Aβ production. Of these, siRNAs targeting PPIL2 (hCyp-60) suppressed β-site cleavage. Knockdown of PPIL2 mRNA decreased BACE1 mRNA, while overexpression of PPIL2 cDNA enhanced BACE1 mRNA levels. Microarray analysis of PPIL2 or BACE1 knockdown indicated that genes affected by BACE1 knockdown are a subset of those dependent upon PPIL2; suggesting that BACE1 expression is downstream of PPIL2. The association of PPIL2 with BACE expression and its requirement for Aβ production suggests new approaches to discover disease modifying agents for AD.

AB - Proteolysis of β-amyloid precursor protein (APP) into amyloid β peptide (Aβ) by β- and γ-secretases is a critical step in the pathogenesis of Alzheimer's Disease (AD), but the pathways regulating secretases are not fully characterized. Ubiquitinylation, which is dysregulated in AD, may affect APP processing. Here, we describe a screen for APP processing modulators using an siRNA library targeting 532 predicted ubiquitin ligases. Seven siRNA pools diminished Aβ production. Of these, siRNAs targeting PPIL2 (hCyp-60) suppressed β-site cleavage. Knockdown of PPIL2 mRNA decreased BACE1 mRNA, while overexpression of PPIL2 cDNA enhanced BACE1 mRNA levels. Microarray analysis of PPIL2 or BACE1 knockdown indicated that genes affected by BACE1 knockdown are a subset of those dependent upon PPIL2; suggesting that BACE1 expression is downstream of PPIL2. The association of PPIL2 with BACE expression and its requirement for Aβ production suggests new approaches to discover disease modifying agents for AD.

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KW - BACE1 regulation

KW - PPIL2

KW - hCyp-60

KW - siRNA screen

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SN - 1044-7431

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JO - Molecular and Cellular Neuroscience

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IS - 3

ER -

A genome wide analysis of ubiquitin ligases in APP processing identifies a novel regulator of BACE1 mRNA levels

Abstract

Keywords

ASJC Scopus subject areas

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