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A paired RNAi and RabGAP overexpression screen identifies Rab11 as a regulator of β-amyloid production.

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posted on 26.12.2013 by Vinod Udayar, Virginie Buggia-Prévot, Rita L. Guerreiro, Gabriele Siegel, Naresh Rambabu, Amanda L Soohoo, Moorthi Ponnusamy, Barbara Siegenthaler, Jitin Bali, Alzheimer’s Exome Sequencing Group, University College London, Mikael Simons, Jonas Ries, Manojkumar Puthenveedu, John Hardy, Gopal Thinakaran, Lawrence Rajendran

Alzheimer's disease (AD) is characterized by cerebral deposition of β-amyloid (Aβ) peptides, which are generated from amyloid precursor protein (APP) by β- and γ-secretases. APP and the secretases are membrane associated, but whether membrane trafficking controls Aβ levels is unclear. Here, we performed an RNAi screen of all human Rab-GTPases, which regulate membrane trafficking, complemented with a Rab-GTPase-activating protein screen, and present a road map of the membrane-trafficking events regulating Aβ production. We identify Rab11 and Rab3 as key players. Although retromers and retromer-associated proteins control APP recycling, we show that Rab11 controlled β-secretase endosomal recycling to the plasma membrane and thus affected Aβ production. Exome sequencing revealed a significant genetic association of Rab11A with late-onset AD, and network analysis identified Rab11A and Rab11B as components of the late-onset AD risk network, suggesting a causal link between Rab11 and AD. Our results reveal trafficking pathways that regulate Aβ levels and show how systems biology approaches can unravel the molecular complexity underlying AD.

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This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-No Derivative Works License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited.

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26/12/2013

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