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 (QaSyn) to the albumin quotient (Qalbumin) 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 QaSyn did not rise or fall with Qalbumin 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.

Small cisterno-lumbar gradient of phosphorylated Tau protein in geriatric patients with suspected normal pressure hydrocephalus

“…In two of these three samples from this patient, the pTau and Tau concentrations in cistern-near were higher than in lumbar CSF supporting our concept of a small cisterno-lumbar gradient of pTau and Tau. Similar rostro-caudal gradients have been found for α-synuclein and NSE in 5 patients with NPH [8]. In contrast to the small cisterno-lumbar concentration differences for pTau and Tau found in fractions 8 and 1 in the present study, the ventriculo-lumbar concentration ratios in NPH patients for Tau and pTau were previously found to be approximately five and twofold, respectively [11–13].…”

Quantification of CSF biomarkers using an electrochemiluminescence-based detection system in the differential diagnosis of AD and sCJD

“…Since Tau has been extensively reported to be a marker of neuronal/axonal injury [6] and sCJD presents increased neuronal damage when compared to AD, it is tempting to speculate that a-synuclein could reflect the extent of synaptic damage in a similar manner as Tau reflects the extent of neuronal damage. In this line, we recently described that human a-synuclein in the CSF is mainly derived from neurons of the brain and spinal cord [22].…”

The Connected Steady State Model and the Interdependence of the CSF Proteome and CSF Flow Characteristics

“…Brain-derived proteins: Tau, Microtubule-associated protein tau; S100B, Protein S100-B; NSE, Gamma-enolase; uniprot IDs: P05060, Secretogranin-1; Q06481, Amyloid-like protein 2. Blood-derived protein: Albumin, Serum albumin .* Values derived from Brandner et al (2014), intra-individual sample pairs were used .*I Samples were obtained from patients suffering from NPH, lumbar CSF was collected 2 days before ventriculostomy and ventricle CSF during surgery .*II Ventricle and lumbar CSF samples of patients suffering from posttraumatic hydrocephalus (PTH) were collected simultaneously at least 8 days after the last surgical or traumatic procedure .** Values derived from Reiber (2001), lumbar CSF samples were taken for routine analysis, ventricle CSF samples were extracted from a drainage from not precisely specified collectives .*** Values derived from Mollenhauer et al (2012), serially collected lumbar CSF fractions (30–35th ml/1–5th ml) of five NPH patients .**** Values derived from Aasebø et al (2014), serially collected lumbar CSF fractions (44–45th mL/1–2nd ml) from a patient suffering from progressive supranuclear palsy (PSP); for reasons of representation the sample ratios were reversed in contrast to the original study. The samples were investigated by mass spectrometry, and quantified by iTRAQ, typical brain-derived proteins showed a ratio ~1, blood-derived proteins <1, no proteins with a considerably reversed gradient were detected indicating that the concentration of brain-derived proteins remain constant in the spinal CSF .…”