Dataset Information

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

ABSTRACT: Alzheimer's disease (AD) is characterized by cerebral deposition of ?-amyloid (A?) peptides, which are generated from amyloid precursor protein (APP) by ?- and ?-secretases. APP and the secretases are membrane associated, but whether membrane trafficking controls A? 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 A? production. We identify Rab11 and Rab3 as key players. Although retromers and retromer-associated proteins control APP recycling, we show that Rab11 controlled ?-secretase endosomal recycling to the plasma membrane and thus affected A? 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 A? levels and show how systems biology approaches can unravel the molecular complexity underlying AD.

SUBMITTER: Udayar V

PROVIDER: S-EPMC4004174 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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

Udayar Vinod V Buggia-Prévot Virginie V Guerreiro Rita L RL Siegel Gabriele G Rambabu Naresh N Soohoo Amanda L AL Ponnusamy Moorthi M Siegenthaler Barbara B Bali Jitin J Simons Mikael M Ries Jonas J Puthenveedu Manojkumar A MA Hardy John J Thinakaran Gopal G Rajendran Lawrence L

Cell reports 20131201 6

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 r ...[more]

PMID: 24373285

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Project description:Glioblastoma multiforme is the most common and most aggressive type of primary brain tumor. The brain-infiltrative character of glioblastoma makes complete surgical removal of the tumor impossible and neither radiation nor current chemotherapy provide cure. Recent evidence shows that glioblastoma multiforme consists of heterogeneous cell populations which differ in tumor-forming potential. Enriched tumor-initiating capacity has been linked to poorly differentiated glioblastoma cells sharing features with neural stem cells. Thus, these cells are important targets for new therapeutic strategies. We aim to identify novel targets controlling maintenance and differentiation in glioblastoma-initiating cells through high throughput screening. To this end, we utilized libraries of small chemical compounds and small interference RNAs in combination with automated imaging and data analysis. Patient-derived glioblastoma cells were expanded and characterized using neural stem cell conditions. In culture, the cells showed low differentiation but expression of neural stem cell markers such as Nestin and Sox2. Upon intracranial injection into SCID mice these cells gave rise to tumors displaying the hallmarks of the human disease. Differentiation of glioblastoma-initiating cells (for example elicited through bone morphogenetic protein, BMP) was associated with strong morphological changes. Hence, cellular morphology, as well as markers specific for differentiation or death were used as screen readout. Lentiviral RNA interference-based screening yielded several gene knockdowns leading to ‘forced’ differentiation of glioblastoma-initiating cells. For example, knockdown of TRRAP (transformation/transcription domain associated protein) led to strongly increased differentiation and loss of proliferative and self-renewing capacity in these cells. TRRAP is an adapter protein implicated in oncogenic transformation through c-MYC transcription activation, also participating in chromatin remodeling and DNA repair. Glioblastoma-initiating cells with reduced TRRAP displayed increased apoptosis upon treatment with the genotoxic agent temozolomide. In vivo, Trapp knockdown cells were not able to give rise to glioblastoma upon transplantation into the brain of SCID mice. Together, these findings support a crucial role for TRRAP in maintenance and tumorigenicity of glioblastoma-initiating cells and might offer future therapeutic options. Two treatments compared to control: two different shRNA sequences for TRRAP were compared to a control shRNA sequence in their effects on global transcription in brain tumor initiating cells

Dataset Information

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

Publications

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

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