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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    • "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.
    Fluids and Barriers of the CNS 07/2014; 11(1):17. DOI:10.1186/2045-8118-11-17
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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.
    PLoS ONE 12/2013; 8(12):e83914. DOI:10.1371/journal.pone.0083914 · 3.23 Impact Factor
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    • "It has been shown that under normal conditions full length α-Syn is detected in CSF [7,26]. Investigation of its origin in CSF has shown that despite its higher levels in peripheral blood products, neurons of the brain and the spinal cord represent the principal source of α-Syn in human CSF [8]. Diurnal or sinusoidal fluctuations are not present over 33h [17] either in healthy elderly controls or in patients with AD, while no significant rostro-caudal gradient concentration has been reported [8,27]. "
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    ABSTRACT: The detection of α-synuclein (α-syn) in the cerebrospinal fluid (CSF) of patients with synucleinopathy has yielded promising but inconclusive results. The aim of the present study was to determine the diagnostic value of α-syn as a biological marker for Dementia with Lewy bodies (DLB) vs. normal subjects and patients with Alzheimer's disease (AD), after strict control of several recognized confounders. Sixteen patients with DLB, 18 patients with AD and 22 age- and sex-matched normal controls (CTRL) were recruited. The levels of total α-syn in CSF were measured using a novel enzyme-linked immunosorbent assay. There was a significant increase of CSF α-syn levels in DLB patients as compared to the CTRL and AD groups (P= 0.049 and 0.01 respectively). ROC analysis revealed that increased α-syn was 81.8% specific for the discrimination of DLB vs. CTRL and 90% vs. AD. However, sensitivity was lower (56.2 % and 50% respectively). These findings provide evidence for a possible diagnostic role of α-syn as a surrogate biomarker for DLB.
    PLoS ONE 11/2013; 8(11):e81654. DOI:10.1371/journal.pone.0081654 · 3.23 Impact Factor
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