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


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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    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.
    Preview · Article · Dec 2015 · Brain
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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.
    Full-text · Article · Jul 2014 · Fluids and Barriers of the CNS
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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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    ABSTRACT: Parkinson's disease (PD) is a movement disorder associated with genetic and age related causes. Although autosomal recessive early onset PD linked to parkin mutations does not exhibit α-Synuclein accumulation, while autosomal dominant and sporadic PD manifest with α-Synuclein inclusions, loss of dopaminergic substantia nigra neurons is a common denominator in PD. Here we show that decreased parkin ubiquitination and loss of parkin stability impair interaction with Beclin-1 and alter α-Synuclein degradation, leading to death of dopaminergic neurons. Tyrosine kinase inhibition increases parkin ubiquitination and interaction with Beclin-1, promoting autophagic α-Synuclein clearance and nigral neuron survival. However, loss of parkin via deletion increases α-Synuclein in the blood compared to the brain, suggesting that functional parkin prevents α-Synuclein release into the blood. These studies demonstrate that parkin ubiquitination affects its protein stability and E3 ligase activity, possibly leading to α-Synuclein sequestration and subsequent clearance.
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