Dataset Information

Transferrin isoforms in cerebrospinal fluid and their relation to neurological diseases.

ABSTRACT: Iron plays many important roles in the brain, including involvement in myelination, neurotransmission and electron transfer in the respiratory chain. Transferrin (Tf), an iron transporter, is mainly biosynthesized in the liver, but can also be biosynthesized in the brain; i.e., by oligodendrocytes and the choroid plexus, a cerebrospinal fluid (CSF) producing tissue. The CSF contains two Tf isoforms, brain-type Tf and serum-type Tf, which differ in their glycan structures. Brain-type Tf is uniquely glycolsylated with biantennary asialo- and agalacto-complex type N-glycans that carry bisecting ?1,4-GlcNAc and core ?1,6-Fuc. The glycans of serum-type Tf in the CSF are similar to those of Tf in serum. Biochemical analyses reveal that the apparent molecular size of brain-type Tf is smaller than that of serum-type Tf, and that hydrophobic patches are exposed on brain-type Tf as demonstrated by hydrophobic probe binding studies. We found that brain-type Tf levels were decreased in idiopathic normal pressure hydrocephalus, in which CSF production is suspected to decrease, while brain-type Tf increased in spontaneous intracranial hypotension, in which CSF production is suspected to increase. These results suggest that brain-type Tf could be a biomarker of altered CSF production.

SUBMITTER: Murakami Y

PROVIDER: S-EPMC6742728 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Transferrin isoforms in cerebrospinal fluid and their relation to neurological diseases.

Murakami Yuta Y Saito Kiyoshi K Ito Hiromi H Hashimoto Yasuhiro Y

Proceedings of the Japan Academy. Series B, Physical and biological sciences 20190101 5

Iron plays many important roles in the brain, including involvement in myelination, neurotransmission and electron transfer in the respiratory chain. Transferrin (Tf), an iron transporter, is mainly biosynthesized in the liver, but can also be biosynthesized in the brain; i.e., by oligodendrocytes and the choroid plexus, a cerebrospinal fluid (CSF) producing tissue. The CSF contains two Tf isoforms, brain-type Tf and serum-type Tf, which differ in their glycan structures. Brain-type Tf is unique ...[more]

PMID: 31080188

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Project description:Neurodegenerative diseases, such as multiple sclerosis represent global health issues. Accordingly, there is an urgent need to understand the pathogenesis of this and other central nervous system disorders, so that more effective therapeutics can be developed. Cerebrospinal fluid is a potential source of important reporter molecules released from various cell types as a result of central nervous system pathology. Here, we report the development of an unbiased approach for the detection of reactive cerebrospinal fluid molecules and target brain proteins from patients with multiple sclerosis. To help identify molecules that may serve as clinical biomarkers for multiple sclerosis, we have biotinylated proteins present in the cerebrospinal fluid and tested their reactivity against brain homogenate as well as myelin and myelin-axolemmal complexes. Proteins were separated by two-dimensional gel electrophoresis, blotted onto membranes and probed separately with biotinylated unprocessed cerebrospinal fluid samples. Protein spots that reacted to two or more multiple sclerosis-cerebrospinal fluids were further analyzed by matrix assisted laser desorption ionization-time-of-flight time-of-flight mass spectrometry. In addition to previously reported proteins found in multiple sclerosis cerebrospinal fluid, such as ?? crystallin, enolase, and 14-3-3-protein, we have identified several additional molecules involved in mitochondrial and energy metabolism, myelin gene expression and/or cytoskeletal organization. These include aspartate aminotransferase, cyclophilin-A, quaking protein, collapsin response mediator protein-2, ubiquitin carboxy-terminal hydrolase L1, and cofilin. To further validate these findings, the cellular expression pattern of collapsin response mediator protein-2 and ubiquitin carboxy-terminal hydrolase L1 were investigated in human chronic-active MS lesions by immunohistochemistry. The observation that in multiple sclerosis lesions phosphorylated collapsin response mediator protein-2 was increased, whereas Ubiquitin carboxy-terminal hydrolase L1 was down-regulated, not only highlights the importance of these molecules in the pathology of this disease, but also illustrates the use of our approach in attempting to decipher the complex pathological processes leading to multiple sclerosis and other neurodegenerative diseases.

Project description:BACKGROUND:The human APOE gene, which codes for apolipoprotein E (apoE), has three major polymorphic alleles: ?2, ?3, and ?4 that give rise to amino acid substitutions. APOE-?4 is a strong risk factor of sporadic Alzheimer's disease (AD) but the reason why is still unknown despite intense research for more than 20?years. The aim of the study was to investigate if the concentrations of total apoE and the specific apoE isoforms in cerebrospinal fluid (CSF) differ between various neurodegenerative diseases and control individuals, as well as among the APOE genotypes. METHODS:Quantification of total apoE and specific apoE isoforms (E2, E3, and E4) in CSF was performed using high-resolution parallel reaction monitoring mass spectrometry. In total, 1820 individuals were involved in the study including clinically diagnosed AD patients (n?=?228), cognitively unimpaired (CU) patients (n?=?896), and patients with other neurodegenerative disorders (n?=?696). Follow-up data was available for 100 individuals, assessed at two time points. Subjects were dichotomized based on an A?42/40 CSF concentration ratio cut-off into A? positive (A?+, <?0.091) and A? negative (A?-, >?0.091) groups. RESULTS:Even though there was a significant increase of total apoE in the amyloid ?-positive (A?+) group compared with amyloid ?-negative (A?-) individuals (p?<?0.001), the magnitude of the effect was very small (AUC?=?0.55). Moreover, CSF total apoE concentrations did not differ between A?- CU controls and clinically diagnosed AD patients. There was a difference in concentration between isoforms in heterozygous individuals in an isoform-dependent manner (E2?<?E3?<?E4) (p?<?0.001, AUC?=?0.64-0.69), and these associations remained when dichotomizing the samples into A?+ and A?- groups (p?<?0.01, AUC?=?0.63-0.74). In the cohort with follow-up samples, neither total apoE nor isoform-specific apoE concentrations differed between the two time points (p?>?0.05). CONCLUSIONS:The results indicate that neither the concentrations of total apoE nor the different apoE isoforms in CSF are associated with APOE-?4 carrier status, A? status, or clinical dementia diagnoses.

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Dataset Information

Transferrin isoforms in cerebrospinal fluid and their relation to neurological diseases.

Publications

Transferrin isoforms in cerebrospinal fluid and their relation to neurological diseases.

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