Article

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

Paracelsus-Elena-Klinik, Klinikstrasse 16, 34128, Kassel, Germany.
Journal of Neural Transmission (Impact Factor: 2.4). 03/2012; 119(7):739-46. DOI: 10.1007/s00702-012-0784-0
Source: PubMed

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.

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    • "Although a-synuclein does not contain a sorting signal for extracellular release, soluble and aggregated a-synuclein was detected in tissue culture medium and body fluids, such as brain interstitial fluid, plasma and CSF (El-Agnaf et al., 2003, 2006; Lee et al., 2005, 2014; Tokuda et al., 2010; Emmanouilidou et al., 2011; Hansson et al., 2014). Extracellular a-synuclein was subsequently studied as a potential diagnostic biomarker, especially in the CSF, where the majority of a-synuclein is derived from the CNS rather than from peripheral blood (Mollenhauer et al., 2012). Most studies have shown a reduction of CSF a-synuclein levels in Parkinson's disease and dementia with Lewy bodies (Tokuda et al., 2006; Hong et al., 2010; Mollenhauer et al., 2011); however, conflicting results with either no differences compared to controls or even increased levels of extracellular a-synuclein were reported (Noguchi-Shinohara et al., 2009; Ohrfelt et al., 2009; Reesink et al., 2010). "
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    • "It has been suggested that most of the a-Syn found in the brain and CSF is produced by neurons and/or neuroglia [39]. Yet, a smaller, secondary source of a-Syn may originate from transport from the blood to CSF (Figure 1). "
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    ABSTRACT: Parkinson's disease (PD) is a neurodegenerative disorder characterized by the accumulation of α-Synuclein (a-Syn) into Lewy body inclusions and the loss of dopaminergic neurons in the substantia nigra (SN). Accumulation of a-Syn can induce a progressive, cyclical pathology that results in the transmission of toxic, aggregated a-Syn species to healthy neurons, leading to further neurodegeneration such as occurs in PD. The blood-brain barrier (BBB) and blood-cerebrospinal fluid (CSF) barriers (BCSFB) are responsible for regulating the access of nutrients and other molecules to the brain, but very little is known about their regulatory roles in maintaining the homeostasis of a-Syn in the CSF and brain parenchyma. This review analyzes the current literature reports on the transport of a-Syn by various brain cell types with a particular focus on the potential transport mechanisms of a-Syn at the BBB and BCSFB. The indication of altered a-Syn transport by brain barriers in PD pathoetiology and the perspectives in this research area are also discussed.
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    • "Taken together, these data suggest that parkin-linked PD cases may have no LB inclusions due to failure of α-Synuclein sequestration en route to autophagic degradation. Although cerebrospinal fluid (CSF) α-Synuclein is thought to be derived from the brain in sporadic PD [60], it is unknown whether there is a difference in the level of α-Synuclein in the blood or CSF between parkin-linked mutations and sporadic PD. Parkin inactivation due to decreased solubility and reduced enzymatic activity [26], [27], [28] may result in α-Synuclein accumulation and LB formation over time in sporadic PD. "
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