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- Curtis, Bruce A., et al.
(författare)
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Algal genomes reveal evolutionary mosaicism and the fate of nucleomorphs
- 2012
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 492:7427, s. 59-65
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Tidskriftsartikel (refereegranskat)abstract
- Cryptophyte and chlorarachniophyte algae are transitional forms in the widespread secondary endosymbiotic acquisition of photosynthesis by engulfment of eukaryotic algae. Unlike most secondary plastid-bearing algae, miniaturized versions of the endosymbiont nuclei (nucleomorphs) persist in cryptophytes and chlorarachniophytes. To determine why, and to address other fundamental questions about eukaryote-eukaryote endosymbiosis, we sequenced the nuclear genomes of the cryptophyte Guillardia theta and the chlorarachniophyte Bigelowiella natans. Both genomes have >21,000 protein genes and are intron rich, and B. natans exhibits unprecedented alternative splicing for a single-celled organism. Phylogenomic analyses and subcellular targeting predictions reveal extensive genetic and biochemical mosaicism, with both host-and endosymbiont-derived genes servicing the mitochondrion, the host cell cytosol, the plastid and the remnant endosymbiont cytosol of both algae. Mitochondrion-to-nucleus gene transfer still occurs in both organisms but plastid-to-nucleus and nucleomorph-to-nucleus transfers do not, which explains why a small residue of essential genes remains locked in each nucleomorph.
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- Hanbouch, L., et al.
(författare)
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Specific Mutations in the Cholesterol-Binding Site of APP Alter Its Processing and Favor the Production of Shorter, Less Toxic A beta Peptides
- 2022
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Ingår i: Molecular Neurobiology. - : Springer Science and Business Media LLC. - 0893-7648 .- 1559-1182. ; 59, s. 7056-7073
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Tidskriftsartikel (refereegranskat)abstract
- Excess brain cholesterol is strongly implicated in the pathogenesis of Alzheimer's disease (AD). Here we evaluated how the presence of a cholesterol-binding site (CBS) in the transmembrane and juxtamembrane regions of the amyloid precursor protein (APP) regulates its processing. We generated nine point mutations in the APP gene, changing the charge and/or hydrophobicity of the amino-acids which were previously shown as part of the CBS. Most mutations triggered a reduction of amyloid-beta peptides A beta 40 and A beta 42 secretion from transiently transfected HEK293T cells. Only the mutations at position 28 of A beta in the APP sequence resulted in a concomitant significant increase in the production of shorter A beta peptides. Mass spectrometry (MS) confirmed the predominance of A beta x-33 and A beta x-34 with the APP(K28A) mutant. The enzymatic activity of alpha-, beta-, and gamma-secretases remained unchanged in cells expressing all mutants. Similarly, subcellular localization of the mutants in early endosomes did not differ from the APP(WT) protein. A transient increase of plasma membrane cholesterol enhanced the production of A beta 40 and A beta 42 by APP(WT), an effect absent in APP(K28A) mutant. Finally, WT but not CBS mutant A beta derived peptides bound to cholesterol-rich exosomes. Collectively, the present data revealed a major role of juxtamembrane amino acids of the APP CBS in modulating the production of toxic A beta species. More generally, they underpin the role of cholesterol in the pathophysiology of AD.
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