| 1. |
- Azevedo, Carla, et al.
(författare)
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Parkinsons disease and multiple system atrophy patient iPSC-derived oligodendrocytes exhibit alpha-synuclein-induced changes in maturation and immune reactive properties
- 2022
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 119:12
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Tidskriftsartikel (refereegranskat)abstract
- Limited evidence has shed light on how aSYN proteins affect the oligodendrocyte phenotype and pathogenesis in synucleinopathies that include Parkinsons disease (PD) and multiple system atrophy (MSA). Here, we investigated early transcriptomic changes within PD and MSA O4(+) oligodendrocyte lineage cells (OLCs) generated from patient-induced pluripotent stem cells (iPSCs). We found impaired maturation of PD and MSA O4(+) OLCs compared to controls. This phenotype was associated with changes in the human leukocyte antigen (HLA) genes, the immunoproteasome subunit PSMB9, and the complement component C4b for aSYN p.A53T and MSA O4(+) OLCs, but not in SNCA(trip) O4(+) OLCs despite high levels of aSYN assembly formation. Moreover, SNCA overexpression resulted in the development of O4(+) OLCs, whereas exogenous treatment with aSYN species led to significant toxicity. Notably, transcriptome profiling of genes encoding proteins forming Lewy bodies and glial cytoplasmic inclusions revealed clustering of PD aSYN p.A53T O4(+) OLCs with MSA O4(+) OLCs. Our work identifies early phenotypic and pathogenic changes within human PD and MSA O4(+) OLCs.
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| 2. |
- Paulus, Agnes, et al.
(författare)
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Correlative imaging to resolve molecular structures in individual cells: Substrate validation study for super-resolution infrared microspectroscopy
- 2022
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Ingår i: Nanomedicine: Nanotechnology, Biology and Medicine. - : Elsevier BV. - 1549-9642 .- 1549-9634. ; 43, s. 102563-102563
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Tidskriftsartikel (refereegranskat)abstract
- Light microscopy has been a favorite tool of biological studies for almost a century, recently producing detailed images with exquisite molecular specificity achieving spatial resolution at nanoscale. However, light microscopy is insufficient to provide chemical information as a standalone technique. An increasing amount of evidence demonstrates that optical photothermal infrared microspectroscopy (O-PTIR) is a valuable imaging tool that can extract chemical information to locate molecular structures at submicron resolution. To further investigate the applicability of sub-micron infrared microspectroscopy for biomedical applications, we analyzed the contribution of substrate chemistry to the infrared spectra acquired from individual neurons grown on various imaging substrates. To provide an example of correlative immunofluorescence/O-PTIR imaging, we used immunofluorescence to locate specific organelles for O-PTIR measurement, thus capturing molecular structures at the sub-cellular level directly in cells, which is not possible using traditional infrared microspectroscopy or immunofluorescence microscopy alone.
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| 3. |
- Solomon, Miriam, et al.
(författare)
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Recommendations for addressing the translational gap between experimental and clinical research on amyloid diseases
- 2022
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Ingår i: Journal of Translational Medicine. - : Springer Science and Business Media LLC. - 1479-5876. ; 20:213, s. 1-7
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Tidskriftsartikel (refereegranskat)abstract
- This paper is a report of recommendations for addressing translational challenges in amyloid disease research. They were developed during and following an international online workshop organized by the LINXS Institute of Advanced Neutron and X-Ray Science in March 2021. Key suggestions include improving cross-cultural communication between basic science and clinical research, increasing the influence of scientific societies and journals (vis-à-vis funding agencies and pharmaceutical companies), improving the dissemination of negative results, and strengthening the ethos of science.
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| 4. |
- Vosough, Faraz, 1986-
(författare)
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Structure and dynamics of amyloid-beta oligomers
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Alzheimer's disease (AD) is the most common cause of dementia, affects tens of millions of people all over the world and inflicts huge socioeconomic costs on the societies. AD is a neurodegenerative disease; it progresses over time and is highly debilitating at the advanced stages. Biochemical and genetic studies in the last decades have revealed that amyloid-beta (Aβ) peptides play underlying roles in the molecular pathology of AD. Aβ peptides are small, aggregation-prone polypeptides produced in the neural tissue. Soluble aggregates of Aβ peptides, known as Aβ oligomers are regarded as the major neurotoxic species in AD brain.In this thesis, in vitro studies were performed on Aβ oligomers with a number of spectroscopy and biochemical methods. The main technique used in this thesis is infrared (IR) spectroscopy, a variety of vibrational spectroscopy methods. IR spectroscopy measures the absorption of IR radiation by the vibrational transitions of oscillating dipoles within chemical structures and provides structural information on chemical bonds and functional groups in molecules. The method can provide valuable data on the secondary structure of proteins and therefore is a powerful tool for studying protein self-assembly and aggregation.Different samples of homogeneous and heterogeneous Aβ42 oligomers were prepared and studied with IR spectroscopy and biochemical methods to establish correlations between oligomers' physical properties (size and homogeneity) and IR parameters. Additionally, the effects of lithium and nickel ions on the formation of homogeneous Aβ42 oligomers were studied. Separately, isotope-edited IR spectroscopy was used to study the molecular structure of homogeneous and heterogeneous Aβ42 oligomers. The obtained data can be helpful to establish IR spectroscopy for characterization of Aβ oligomers, as well as studies on their dynamics and interactions with each other and other biomolecules or inorganic materials. Moreover, the findings in this thesis add to the available knowledge on the molecular structure of Aβ oligomers and help to develop relevant molecular models. Such information can be helpful for the development of diagnostics and therapeutic strategies for AD.
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