The Golgi-Localized γ-Ear-Containing ARF-Binding (GGA) Proteins Alter Amyloid-β Precursor Protein (APP) Processing through Interaction of Their GAE Domain with the Beta-Site APP Cleaving Enzyme 1 (BACE1)

Einem, Bjoern von; Wahler, Anke; Schips, Tobias G.; Serrano-Pozo, Alberto; Proepper, Christian; Boeckers, Tobias M.; Rueck, Angelika C.; Wirth, Thomas; Hyman, Bradley T.; Danzer, Karin M; Thal, Dietmar Rudolf; Arnim, Christine A. F. Von

doi:10.1371/journal.pone.0129047

Cited by 19 publications

(13 citation statements)

References 67 publications

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“…The GGA family genes were implicated in both PG and GG; GGA2 was downregulated in both and GGA3 upregulated in the GG. GGA depletion has been shown to have a missorting effect on mannose‐6‐phosphate receptors, cathepsin D and APP secretory inhibition, which was one of the top hits in our master gene list. In HeLa cells, it was found that overexpression of GGA's increases fragmentation and vacuolization of the trans‐Golgi network implying that these proteins have a role in maintaining Golgi integrity .…”

Section: Resultsmentioning

confidence: 99%

Meta‐Analysis of Publicly Available Chinese Hamster Ovary (CHO) Cell Transcriptomic Datasets for Identifying Engineering Targets to Enhance Recombinant Protein Yields

Tamošaitis

Smales

2018

Biotechnology Journal

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Transcriptomics has been extensively applied to the investigation of the CHO cell platform for the production of recombinant biotherapeutic proteins to identify transcripts whose expression is regulated and correlated to (non)desirable CHO cell attributes. However, there have been few attempts to analyze the findings across these studies to identify conserved changes and generic targets for CHO cell platform engineering. Here, the authors have undertaken a meta-analysis of CHO cell transcriptomic data and report on those genes most frequently identified as differentially expressed with regard to cell growth (μ) and productivity (Qp). By aggregating differentially expressed genes from publicly available transcriptomic datasets associated with μ and Qp, using a pathway enrichment analysis and combining it with the concordance of gene expression values, the authors have identified a refined target gene and pathway list while determining the overlap across CHO transcriptomic studies. The authors find that only the cell cycle and lysosome pathways show good concordance. By mapping out the contributing genes the authors have constructed a transcriptomic "fingerprint" of a high-performing cell line. This study provides a starting resource for researchers who want to navigate the complex landscape of CHO transcriptomics and identify targets to undertake cell engineering for improved recombinant protein output.

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Section: Resultsmentioning

confidence: 99%

Meta‐Analysis of Publicly Available Chinese Hamster Ovary (CHO) Cell Transcriptomic Datasets for Identifying Engineering Targets to Enhance Recombinant Protein Yields

Tamošaitis

Smales

2018

Biotechnology Journal

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“…The yeast GGA1 protein has been implicated in binding ubiquitin, thus facilitating the sorting of cargo proteins from the trans-Golgi network to endosomal compartments (Takatsu et al, 2002; Zhdankina et al, 2001). Human GGA1 overexpression attenuates amyloidogenic processing of amyloid precursor proteins (APP) in Alzheimer’s disease and a rare inherited lipid-storage disease, Niemann-Pick type C (NPC) (Kosicek et al, 2014; von Einem et al, 2015). Finally, SIS1 , the yeast Hsp40 homolog of human DNAJ/HSP40 family proteins, was identified as αSyn suppressor via PRISM.…”

Section: Resultsmentioning

confidence: 99%

Randomized CRISPR-Cas Transcriptional Perturbation Screening Reveals Protective Genes against Alpha-Synuclein Toxicity

et al. 2017

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SUMMARY The genome-wide perturbation of transcriptional networks with CRISPR-Cas technology has primarily involved systematic and targeted gene modulation. Here, we developed PRISM (Perturbing Regulatory Interactions by Synthetic Modulators), a screening platform that uses randomized CRISPR-Cas transcription factors (crisprTFs) to globally perturb transcriptional networks. By applying PRISM to a yeast model of Parkinson’s disease (PD), we identified guide RNAs (gRNAs) that modulate transcriptional networks and protect cells from alpha-synuclein (αSyn) toxicity. One gRNA identified in this screen outperformed the most protective suppressors of αSyn toxicity reported previously, highlighting PRISM’s ability to identify modulators of important phenotypes. Gene expression profiling revealed genes differentially modulated by this strong protective gRNA that rescued yeast from αSyn toxicity when overexpressed. Human homologs of top-ranked hits protected against αSyn-induced cell death in a human neuronal PD model. Thus, high-throughput and unbiased perturbation of transcriptional networks via randomized crisprTFs can reveal complex biological phenotypes and effective disease modulators.

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“…APP695 CMV(myc) is described in Kinoshita et al [30]. BACE-phCMV3(HA) is described in von Einem et al [31]. pUltra-hot is a lentiviral vector backbone for bi-cistronic expression of the gene of interest and the fluorescent reporter mCherry under the control of a human ubiquitin promoter.…”

Section: Methodsmentioning

confidence: 99%

Metabolic Characterization of Intact Cells Reveals Intracellular Amyloid Beta but Not Its Precursor Protein to Reduce Mitochondrial Respiration

et al. 2016

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One hallmark of Alzheimer´s disease are senile plaques consisting of amyloid beta (Aβ), which derives from the processing of the amyloid precursor protein (APP). Mitochondrial dysfunction has been linked to the pathogenesis of Alzheimer´s disease and both Aβ and APP have been reported to affect mitochondrial function in isolated systems. However, in intact cells, considering a physiological localization of APP and Aβ, it is pending what triggers the mitochondrial defect. Thus, the aim of this study was to dissect the impact of APP versus Aβ in inducing mitochondrial alterations with respect to their subcellular localization. We performed an overexpression of APP or beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), increasing APP and Aβ levels or Aβ alone, respectively. Conducting a comprehensive metabolic characterization we demonstrate that only APP overexpression reduced mitochondrial respiration, despite lower extracellular Aβ levels compared to BACE overexpression. Surprisingly, this could be rescued by a gamma secretase inhibitor, oppositionally indicating an Aβ-mediated mitochondrial toxicity. Analyzing Aβ localization revealed that intracellular levels of Aβ and an increased spatial association of APP/Aβ with mitochondria are associated with reduced mitochondrial respiration. Thus, our data provide marked evidence for a prominent role of intracellular Aβ accumulation in Alzheimer´s disease associated mitochondrial dysfunction. Thereby it highlights the importance of the localization of APP processing and intracellular transport as a decisive factor for mitochondrial function, linking two prominent hallmarks of neurodegenerative diseases.

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The Golgi-Localized γ-Ear-Containing ARF-Binding (GGA) Proteins Alter Amyloid-β Precursor Protein (APP) Processing through Interaction of Their GAE Domain with the Beta-Site APP Cleaving Enzyme 1 (BACE1)

Cited by 19 publications

References 67 publications

Meta‐Analysis of Publicly Available Chinese Hamster Ovary (CHO) Cell Transcriptomic Datasets for Identifying Engineering Targets to Enhance Recombinant Protein Yields

Meta‐Analysis of Publicly Available Chinese Hamster Ovary (CHO) Cell Transcriptomic Datasets for Identifying Engineering Targets to Enhance Recombinant Protein Yields

Randomized CRISPR-Cas Transcriptional Perturbation Screening Reveals Protective Genes against Alpha-Synuclein Toxicity

Metabolic Characterization of Intact Cells Reveals Intracellular Amyloid Beta but Not Its Precursor Protein to Reduce Mitochondrial Respiration

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