144819 20240826163725.0 10.53846/goediss-5944 doi DZNE-2020-00261 English Stündl, Anne-Katrin P:(DE-2719)2811738 0 First author dzne Characterization of exosomes as a diagnostic marker in neurodegenerative diseases - 2016-08-16 2016 95 pages : illustrations, XII Output Types/Dissertation DataCite DISSERTATION ORCID PHDTHESIS BibTeX Thesis 2 EndNote Dissertation / PhD Thesis phd phd PUB:(DE-HGF)11 1724680275_22476 PUB:(DE-HGF) doctoralThesis DRIVER Dissertation, Georg-August-Universität zu Göttingen, 2016 Georg-August-Universität zu Göttingen Dissertation 2016 2016-08-16 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. 344 - Clinical and Health Care Research (POF3-344) G:(DE-HGF)POF3-344 POF3-344 POF III 0 Dataset connected to DataCite 10.53846/goediss-5944 https://ediss.uni-goettingen.de/handle/11858/00-1735-0000-002B-7C51-B http://pub.dzne.de/record/144819/files/DZNE-2020-00261.pdf OpenAccess http://pub.dzne.de/record/144819/files/DZNE-2020-00261.pdf?subformat=pdfa pdfa OpenAccess oai:pub.dzne.de:144819 openaire open_access VDB driver dnbdelivery Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 0 P:(DE-2719)2811738 DE-HGF Gesundheit Erkrankungen des Nervensystems G:(DE-HGF)POF3-340 G:(DE-HGF)POF3-344 G:(DE-HGF)POF3 G:(DE-HGF)POF3-300 G:(DE-HGF)POF Clinical and Health Care Research 0 2016 OpenAccess StatID:(DE-HGF)0510 StatID Creative Commons Attribution-NonCommercial-NoDerivs CC BY-NC-ND 4.0 LIC:(DE-HGF)CCBYNCND4 HGFVOC yes I:(DE-2719)1440011 AG Schneider Göttingen Translational Dementia Research Göttingen 0 phd VDB I:(DE-2719)1440011 UNRESTRICTED FullTexts