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- Barbash, S, et al.
(författare)
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Brain gene expression signature on primate genomic sequence evolution
- 2017
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1, s. 17329-
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Tidskriftsartikel (refereegranskat)abstract
- Considering the overwhelming changes that occurred during primate evolution in brain structure and function, one might expect corresponding changes at the molecular level. Surprisingly, a relatively constrained gene expression pattern is observed in brain compared with other tissues among primates, an observation that calls for reassessment of RNA expression influence on primate genome evolution. We built phylogenetic trees based on genomic sequences of functional genomic regions and tissue-specific RNA expression in eight tissue types for six primate species. Comparisons of the phylogenetic trees from brain tissues revealed that DNA- and RNA-based trees were significantly similar. The similarity was specific for promoter regions and cerebellum and frontal cortex expression, suggesting a major impact of gene regulation in the brain on genome shaping along the primate branch.
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| 3. |
- Barbash, S, et al.
(författare)
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Length-dependent gene misexpression is associated with Alzheimer's disease progression
- 2017
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1, s. 190-
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Tidskriftsartikel (refereegranskat)abstract
- Recent reports show transcription preference for long genes in neuronal tissues compared with non-neuronal tissues, and a gene-length dependent change in expression in the neurodevelopmental disease Rett syndrome (RTT). Whether the gene-length dependent changes in expression seen in RTT might also be seen in neurodegenerative diseases is not yet known. However, a reasonable hypothesis is that similar effects might be seen in neurodegenerative diseases as well as in RTT since a common general feature of both illnesses involves progressive dysfunction of synapses. Here, we demonstrate a clear length-dependent gene misexpression in the most prevalent neurodegenerative disease, Alzheimer’s disease. We show that the effect is associated with disease progression and can be attributed specifically to neurons. In particular, we observed gene length-dependent down regulation on the level of the whole tissue and gene length-dependent up regulation on the level of single cells. Our analysis shows that a gene-length effect on expression can be found in degenerative neurological illnesses, such as Alzheimer’s disease. Additional investigation to elucidate the precise mechanism underlying gene-length dependent changes in expression is warranted.
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| 6. |
- Bonito-Oliva, A, et al.
(författare)
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Nucleobindin 1 binds to multiple types of pre-fibrillar amyloid and inhibits fibrillization
- 2017
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7, s. 42880-
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Tidskriftsartikel (refereegranskat)abstract
- During amyloid fibril formation, amyloidogenic polypeptides misfold and self assemble into soluble pre-fibrillar aggregates, i.e., protofibrils, which elongate and mature into insoluble fibrillar aggregates. An emerging class of chaperones, chaperone-like amyloid binding proteins (CLABPs), has been shown to interfere with aggregation of particular misfolded amyloid peptides or proteins. We have discovered that the calcium-binding protein nuclebindin-1 (NUCB1) is a novel CLABP. We show that NUCB1 inhibits aggregation of islet-amyloid polypeptide associated with type 2 diabetes mellitus, a-synuclein associated with Parkinson’s disease, transthyretin V30M mutant associated with familial amyloid polyneuropathy, and Aβ42 associated with Alzheimer’s disease by stabilizing their respective protofibril intermediates. Kinetic studies employing the modeling software AmyloFit show that NUCB1 affects both primary nucleation and secondary nucleation. We hypothesize that NUCB1 binds to the common cross-β-sheet structure of protofibril aggregates to “cap” and stabilize soluble macromolecular complexes. Transmission electron microscopy and atomic force microscopy were employed to characterize the size, shape and volume distribution of multiple sources of NUCB1-capped protofibrils. Interestingly, NUCB1 prevents Aβ42 protofibril toxicity in a cellular assay. NUCB1-stabilized amyloid protofibrils could be used as immunogens to prepare conformation-specific antibodies and as novel tools to develop screens for anti-protofibril diagnostics and therapeutics.
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