title: α-Synuclein in human cerebrospinal fluid is principally derived from neurons of the central nervous system.
abstract: The source of Parkinson disease-linked α-synuclein (aSyn) in human cerebrospinal fluid (CSF) remains unknown. We decided to measure the concentration of aSyn and its gradient in human CSF specimens and compared it with serum to explore its origin. We correlated aSyn concentrations in CSF versus serum (Q(aSyn)) to the albumin quotient (Q(albumin)) to evaluate its relation to blood-CSF barrier function. We also compared aSyn with several other CSF constituents of either central or peripheral sources (or both) including albumin, neuron-specific enolase, β-trace protein and total protein content. Finally, we examined whether aSyn is present within the structures of the choroid plexus (CP). We observed that Q(aSyn) did not rise or fall with Q(albumin) values, a relative measure of blood-CSF barrier integrity. In our CSF gradient analyses, aSyn levels decreased slightly from rostral to caudal fractions, in parallel to the recorded changes for neuron-specific enolase; the opposite trend was recorded for total protein, albumin and β-trace protein. The latter showed higher concentrations in caudal CSF fractions due to the diffusion-mediated transfer of proteins from blood and leptomeninges into CSF in the lower regions of the spine. In postmortem sections of human brain, we detected highly variable aSyn reactivity within the epithelial cell layer of CP in patients diagnosed with a range of neurological diseases; however, in sections of mice that express only human SNCA alleles (and in those without any Snca gene expression), we detected no aSyn signal in the epithelial cells of the CP. We conclude from these complementary results that despite its higher levels in peripheral blood products, neurons of the brain and spinal cord represent the principal source of aSyn in human CSF.
authors.affiliation: Paracelsus-Elena-Klinik, Klinikstrasse 16, 34128, Kassel, Germany. brit.mollenhauer@pk-mx.de
authors.forename: Brit
authors.initials: B
authors.lastname: Mollenhauer
authors.forename: Ellen
authors.initials: E
authors.lastname: Trautmann
authors.forename: Birgit
authors.initials: B
authors.lastname: Otte
authors.forename: Juliana
authors.initials: J
authors.lastname: Ng
authors.forename: Annette
authors.initials: A
authors.lastname: Spreer
authors.forename: Peter
authors.initials: P
authors.lastname: Lange
authors.forename: Friederike
authors.initials: F
authors.lastname: Sixel-Döring
authors.forename: Mansoureh
authors.initials: M
authors.lastname: Hakimi
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Vonsattel
authors.forename: Robert
authors.initials: R
authors.lastname: Nussbaum
authors.forename: Claudia
authors.initials: C
authors.lastname: Trenkwalder
authors.forename: Michael G
authors.initials: MG
authors.lastname: Schlossmacher
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood / Q000134:cerebrospinal fluid; D001921:Brain / Q000378:metabolism*; D002831:Choroid Plexus / Q000378:metabolism*; D005260:Female; D006801:Humans; D006850:Hydrocephalus, Normal Pressure / Q000134:cerebrospinal fluid / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000134:cerebrospinal fluid / Q000378:metabolism; D054834:Lipocalins / Q000134:cerebrospinal fluid / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism*; D010751:Phosphopyruvate Hydratase / Q000134:cerebrospinal fluid / Q000378:metabolism; D051844:alpha-Synuclein / Q000134:cerebrospinal fluid* / Q000378:metabolism
chemical_list: D015415:Biomarkers; D054834:Lipocalins; D051844:alpha-Synuclein; D010751:Phosphopyruvate Hydratase; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase