α-Synuclein in human cerebrospinal fluid is principally derived from neurons of the central nervous system

Brit Mollenhauer,Juliana Ng,Ellen Trautmann,Peter Lange,Michael G Schlossmacher,Jean-Paul Vonsattel,Birgit Otte,Annette Spreer,Claudia Trenkwalder,Friederike Sixel-Döring,Mansoureh Hakimi,Robert Nussbaum

doi:10.1007/s00702-012-0784-0

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.

Highlights

The pathological hallmarks of Parkinson disease (PD) include progressive cell loss of selective nuclei in the nervous system and the formation of intracellular aggregates that contain insoluble, wild-type a-synuclein (Spillantini et al 1997)
The quantification of the 140 amino acid-long, 16–17 kDa aSyn protein in biological fluids has been proposed as a biomarker candidate (Mollenhauer et al 2010). aSyn has been shown to be present in cerebrospinal fluid (CSF) in low picogram/ microliter amounts; its levels in serum and plasma are up to tenfold and in whole blood up to 10,000-fold higher (Mollenhauer et al 2010) due to the fact that aSyn is abundantly expressed in the hematopoietic system (Scherzer et al 2008)
Because albumin is solely synthesized in the liver, the quotient of its CSF-to-serum concentrations reflects an indirect measure of blood–CSF barrier function in vivo

Summary

Introduction

The pathological hallmarks of Parkinson disease (PD) include progressive cell loss of selective nuclei in the nervous system and the formation of intracellular aggregates that contain insoluble, wild-type a-synuclein (aSyn) (Spillantini et al 1997). We quantified aSyn levels in patients with normal blood–CSF barrier function and compared them to specific brain-derived (e.g., NSE), blood-derived (e.g., albumin), and leptomeninges-derived (e.g., b-trace) proteins in serially collected CSF samples, to examine their rostro-caudal concentration gradients.

Results

Conclusion