title: Induction of α-synuclein aggregate formation by CSF exosomes from patients with Parkinson's disease and dementia with Lewy bodies.
abstract: Extracellular α-synuclein has been proposed as a crucial mechanism for induction of pathological aggregate formation in previously healthy cells. In vitro, extracellular α-synuclein is partially associated with exosomal vesicles. Recently, we have provided evidence that exosomal α-synuclein is present in the central nervous system in vivo. We hypothesized that exosomal α-synuclein species from patients with α-synuclein related neurodegeneration serve as carriers for interneuronal disease transmission. We isolated exosomes from cerebrospinal fluid from patients with Parkinson's disease, dementia with Lewy bodies, progressive supranuclear palsy as a non-α-synuclein related disorder that clinically overlaps with Parkinson's disease, and neurological controls. Cerebrospinal fluid exosome numbers, α-synuclein protein content of cerebrospinal fluid exosomes and their potential to induce oligomerization of α-synuclein were analysed. The quantification of cerebrospinal fluid exosomal α-synuclein showed distinct differences between patients with Parkinson's disease and dementia with Lewy bodies. In addition, exosomal α-synuclein levels correlated with the severity of cognitive impairment in cross-sectional samples from patients with dementia with Lewy bodies. Importantly, cerebrospinal fluid exosomes derived from Parkinson's disease and dementia with Lewy bodies induce oligomerization of α-synuclein in a reporter cell line in a dose-dependent manner. Our data suggest that cerebrospinal fluid exosomes from patients with Parkinson's disease and dementia with Lewy bodies contain a pathogenic species of α-synuclein, which could initiate oligomerization of soluble α-synuclein in target cells and confer disease pathology.
authors.affiliation: 1 Department of Psychiatry and Psychotherapy, University Medicine Göttingen, Von-Siebold-Str. 5, 37075 Göttingen, Germany 2 Max-Planck-Institute for Experimental Medicine, Hermann-Rein-Str. 3, 37075 Göttingen, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Stuendl
authors.affiliation: 1 Department of Psychiatry and Psychotherapy, University Medicine Göttingen, Von-Siebold-Str. 5, 37075 Göttingen, Germany 2 Max-Planck-Institute for Experimental Medicine, Hermann-Rein-Str. 3, 37075 Göttingen, Germany 3 Cluster of Excellence 'Nanoscale Microscopy and Molecular Physiology of the Brain' (CNMPB), Göttingen, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Kunadt
authors.affiliation: 4 Department of Neuropathology, University Medicine Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany.
authors.forename: Niels
authors.initials: N
authors.lastname: Kruse
authors.affiliation: 1 Department of Psychiatry and Psychotherapy, University Medicine Göttingen, Von-Siebold-Str. 5, 37075 Göttingen, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Bartels
authors.affiliation: 2 Max-Planck-Institute for Experimental Medicine, Hermann-Rein-Str. 3, 37075 Göttingen, Germany.
authors.forename: Wiebke
authors.initials: W
authors.lastname: Moebius
authors.affiliation: 5 Department of Neurology, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany.
authors.forename: Karin M
authors.initials: KM
authors.lastname: Danzer
authors.affiliation: 4 Department of Neuropathology, University Medicine Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany 6 Paracelsus-Elena Klinik, Klinikstr. 16, 34128 Kassel, Germany.
authors.forename: Brit
authors.initials: B
authors.lastname: Mollenhauer
authors.affiliation: 1 Department of Psychiatry and Psychotherapy, University Medicine Göttingen, Von-Siebold-Str. 5, 37075 Göttingen, Germany 2 Max-Planck-Institute for Experimental Medicine, Hermann-Rein-Str. 3, 37075 Göttingen, Germany 3 Cluster of Excellence 'Nanoscale Microscopy and Molecular Physiology of the Brain' (CNMPB), Göttingen, Germany 7 German Centre for Neurodegenerative Diseases (DZNE), Göttingen, Von-Siebold-Str. 5, 37075 Göttingen, Germany anja.schneider@dzne.de.
authors.forename: Anja
authors.initials: A
authors.lastname: Schneider
mesh_terms: D002555:Cerebrospinal Fluid / Q000378:metabolism; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D055354:Exosomes / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D020961:Lewy Body Disease / Q000134:cerebrospinal fluid* / Q000378:metabolism; D008137:Longitudinal Studies; D008297:Male; D010300:Parkinson Disease / Q000134:cerebrospinal fluid* / Q000378:metabolism; D066329:Protein Aggregates / Q000502:physiology*; D051844:alpha-Synuclein / Q000096:biosynthesis / Q000134:cerebrospinal fluid*
chemical_list: D066329:Protein Aggregates; D051844:alpha-Synuclein
keywords: Parkinson’s disease; cerebrospinal fluid; exosomes; extracellular vesicles; α-synuclein