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001     144819
005     20240826163725.0
024 7 _ |a 10.53846/goediss-5944
|2 doi
037 _ _ |a DZNE-2020-00261
041 _ _ |a English
100 1 _ |a Stündl, Anne-Katrin
|0 P:(DE-2719)2811738
|b 0
|e First author
|u dzne
245 _ _ |a Characterization of exosomes as a diagnostic marker in neurodegenerative diseases
|f - 2016-08-16
260 _ _ |c 2016
300 _ _ |a 95 pages : illustrations, XII
336 7 _ |a Output Types/Dissertation
|2 DataCite
336 7 _ |a DISSERTATION
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336 7 _ |a PHDTHESIS
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336 7 _ |a Thesis
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336 7 _ |a Dissertation / PhD Thesis
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336 7 _ |a doctoralThesis
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502 _ _ |a Dissertation, Georg-August-Universität zu Göttingen, 2016
|c Georg-August-Universität zu Göttingen
|b Dissertation
|d 2016
|o 2016-08-16
520 _ _ |a α-Synuclein pathology has been hypothesized to propagate in synucleinopathies by intercellular transfer of pathogenic seeds in a prion-like fashion. Extracellular release of α-Synuclein via small extracellular vesicles has been proposed as one of the mechanisms of cell-to-cell disease transmission. In vitro, extracellular α-Synuclein has been detected in exosomal vesicles and we have recently provided evidence that α-Synuclein is present in exosomes in the central nervous system in vivo. We hypothesized that exosomes from patients with α Synuclein related neurodegeneration serve as carriers for interneuronal disease transfer. In this study, we purified exosomes from cerebrospinal fluid from patients with synucleinopathies including Parkinson`s disease and dementia with Lewy bodies, progressive supranuclear palsy as an example of a disease that clinically overlaps with Parkinson`s disease but without underlying α-Synuclein pathology and other neurological controls without neurodegenerative diseases. Exosome numbers and exosomal α-Synuclein levels were quantified and their potential to induce aggregation of soluble α-Synuclein was evaluated. We observed differences in cerebrospinal fluid exosomal α-Synuclein levels between patients with Parkinson`s disease and dementia with Lewy bodies and between dementia with Lewy bodies and controls. In addition, exosomal α-Synuclein levels correlated with cognitive decline and Tau levels as a marker of neurodegeneration in dementia with Lewy bodies. By analyzing exosomal α-Synuclein levels and exosome numbers, we were able to distinguish Parkinson`s disease from dementia with Lewy bodies and controls as well as dementia with Lewy bodies from Parkinson`s disease and controls with high sensitivity and specificity. Importantly, cerebrospinal fluid exosomes from Parkinson`s disease and dementia with Lewy bodies disease patients induced aggregation of α-Synuclein in a reporter cell model, dependent on the amount of exosomal α-Synuclein. Thus, exosomal α-Synuclein could serve as a diagnostic biomarker for α-Synuclein related neurodegenerative diseases and as a progression marker in dementia with Lewy bodies. These findings further indicate that cerebrospinal fluid derived exosomes from patients with Parkinson`s disease and dementia with Lewy bodies contain a pathogenic α-Synuclein species, which induces aggregation of endogenous α-Synuclein in recipient neurons and therefore could transmit disease pathology. Since multiple recent therapy trials in Alzheimer`s disease have failed and therapeutic interventions are most promising in early and even preclinical stages, the accurate identification of patients with Alzheimer`s disease is indispensable. Therefore, diagnostic and prognostic biomarkers are required and identification of such markers would also give insight into the underlying molecular mechanisms of Alzheimer`s disease pathology. Accumulating evidence suggests that dysregulation of processes, which physiologically regulate gene expression, plays an important role in the pathogenesis of neurodegenerative diseases. Additionally, dysregulation of small non-coding RNAs in Alzheimer`s disease brain has been shown in various studies. In our second study, we analyzed the small non-coding RNA composition of exosomes derived from human cerebrospinal fluid in order to test whether exosomal small non-coding RNA profiles can be used as a disease signature for Alzheimer`s disease. Here, we show that genome-wide profiling of cerebrospinal fluid exosomal small non-coding RNA expression reveals a specific small RNA signature which differentiates Alzheimer`s disease from cognitive healthy controls. Thus, our selected set of exosomal small non-coding RNAs could be used as a potential biomarker in the future, replication in a larger validation cohort provided.
536 _ _ |a 344 - Clinical and Health Care Research (POF3-344)
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588 _ _ |a Dataset connected to DataCite
773 _ _ |a 10.53846/goediss-5944
856 4 _ |u https://ediss.uni-goettingen.de/handle/11858/00-1735-0000-002B-7C51-B
856 4 _ |u https://pub.dzne.de/record/144819/files/DZNE-2020-00261.pdf
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856 4 _ |u https://pub.dzne.de/record/144819/files/DZNE-2020-00261.pdf?subformat=pdfa
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910 1 _ |a Deutsches Zentrum für Neurodegenerative Erkrankungen
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913 1 _ |a DE-HGF
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914 1 _ |y 2016
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920 _ _ |l yes
920 1 _ |0 I:(DE-2719)1440011
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|l Translational Dementia Research Göttingen
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980 _ _ |a phd
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