Dataset Information

Novel forms of neurofascin 155 in the central nervous system: alterations in paranodal disruption models and multiple sclerosis.

ABSTRACT: Stability of the myelin-axon unit is achieved, at least in part, by specialized paranodal junctions comprised of the neuronal heterocomplex of contactin and contactin-associated protein and the myelin protein neurofascin 155. In multiple sclerosis, normal distribution of these proteins is altered, resulting in the loss of the insulating myelin and consequently causing axonal dysfunction. Previously, this laboratory reported that mice lacking the myelin-enriched lipid sulphatide are characterized by a progressive deterioration of the paranodal structure. Here, it is shown that this deterioration is preceded by significant loss of neurofascin 155 clustering at the myelin paranode. Interestingly, prolonged electrophoretic separation revealed the existence of two neurofascin 155 bands, neurofascin 155 high and neurofascin 155 low, which are readily observed following N-linked deglycosylation. Neurofascin 155 high is observed at 7 days of age and reaches peak expression at one month of age, while neurofascin 155 low is first observed at 14 days of age and constantly increases until 5 months of age. Studies using conditional neurofascin knockout mice indicated that neurofascin 155 high and neurofascin 155 low are products of the neurofascin gene and are exclusively expressed by oligodendrocytes within the central nervous system. Neurofascin 155 high is a myelin paranodal protein while the distribution of neurofascin 155 low remains to be determined. While neurofascin 155 high levels are significantly reduced in the sulphatide null mice at 15 days, 30 days and 4 months of age, neurofascin 155 low levels remain unaltered. Although maintained at normal levels, neurofascin 155 low is incapable of preserving paranodal structure, thus indicating that neurofascin 155 high is required for paranodal stability. Additionally, comparisons between neurofascin 155 high and neurofascin 155 low in human samples revealed a significant alteration, specifically in multiple sclerosis plaques.

SUBMITTER: Pomicter AD

PROVIDER: S-EPMC2822635 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Novel forms of neurofascin 155 in the central nervous system: alterations in paranodal disruption models and multiple sclerosis.

Pomicter Anthony D AD Shroff Seema M SM Fuss Babette B Sato-Bigbee Carmen C Brophy Peter J PJ Rasband Matthew N MN Bhat Manzoor A MA Dupree Jeffrey L JL

Brain : a journal of neurology 20100203 Pt 2

Stability of the myelin-axon unit is achieved, at least in part, by specialized paranodal junctions comprised of the neuronal heterocomplex of contactin and contactin-associated protein and the myelin protein neurofascin 155. In multiple sclerosis, normal distribution of these proteins is altered, resulting in the loss of the insulating myelin and consequently causing axonal dysfunction. Previously, this laboratory reported that mice lacking the myelin-enriched lipid sulphatide are characterized ...[more]

PMID: 20129933

Similar Datasets

Project description:ObjectiveTo investigate anti-neurofascin 155 (NF155) antibody-positive chronic inflammatory demyelinating polyneuropathy (CIDP).MethodsSera from 50 consecutive CIDP patients diagnosed in our clinic, 32 patients with multiple sclerosis, 40 patients with other neuropathies including 26 with Guillain-Barré syndrome (GBS)/Fisher syndrome, and 30 healthy controls were measured for anti-NF antibodies by flow cytometry using HEK293 cell lines stably expressing human NF155 or NF186. Four additional CIDP patients with anti-NF155 antibodies referred from other clinics were enrolled for clinical characterization.ResultsThe positivity rate for anti-NF155 antibodies in CIDP patients was 18% (9/50), who all showed a predominance of IgG4 subclass. No other subjects were positive, except one GBS patient harboring IgG1 anti-NF155 antibodies. No anti-NF155 antibody carriers had anti-NF186 antibodies. Anti-NF155 antibody-positive CIDP patients had a significantly younger onset age, higher frequency of drop foot, gait disturbance, tremor and distal acquired demyelinating symmetric phenotype, greater cervical root diameter on magnetic resonance imaging neurography, higher cerebrospinal fluid protein levels, and longer distal and F-wave latencies than anti-NF155 antibody-negative patients. Marked symmetric hypertrophy of cervical and lumbosacral roots/plexuses was present in all anti-NF155 antibody-positive CIDP patients examined by neurography. Biopsied sural nerves from two patients with anti-NF155 antibodies demonstrated subperineurial edema and occasional paranodal demyelination, but no vasculitis, inflammatory cell infiltrates, or onion bulbs. Among anti-NF155 antibody-positive patients, treatment responders more frequently had daily oral corticosteroids and/or immunosuppressants in addition to intravenous immunoglobulins than nonresponders did.InterpretationAnti-NF155 antibodies occur in a subset of CIDP patients with distal-dominant involvement and symmetric nerve hypertrophy.

Project description:BACKGROUND:Metabolic alterations, related to cerebral glucose metabolism, brain insulin resistance, and age-induced mitochondrial dysfunction, play an important role in Alzheimer's disease (AD) on both the systemic and central nervous system level. To study the extent and significance of these alterations in AD, quantitative metabolomics was applied to plasma and cerebrospinal fluid (CSF) from clinically well-characterized AD patients and cognitively healthy control subjects. The observed metabolic alterations were associated with core pathological processes of AD to investigate their relation with amyloid pathology and tau-related neurodegeneration. METHODS:In a case-control study of clinical and biomarker-confirmed AD patients (n =?40) and cognitively healthy controls without cerebral AD pathology (n =?34) with paired plasma and CSF samples, we performed metabolic profiling, i.e., untargeted metabolomics and targeted quantification. Targeted quantification focused on identified deregulated pathways highlighted in the untargeted assay, i.e. the TCA cycle, and its anaplerotic pathways, as well as the neuroactive tryptophan and kynurenine pathway. RESULTS:Concentrations of several TCA cycle and beta-oxidation intermediates were higher in plasma of AD patients, whilst amino acid concentrations were significantly lower. Similar alterations in these energy metabolism intermediates were observed in CSF, together with higher concentrations of creatinine, which were strongly correlated with blood-brain barrier permeability. Alterations of several amino acids were associated with CSF Amyloid?1-42. The tryptophan catabolites, kynurenic acid and quinolinic acid, showed significantly higher concentrations in CSF of AD patients, which, together with other tryptophan pathway intermediates, were correlated with either CSF Amyloid?1-42, or tau and phosphorylated Tau-181. CONCLUSIONS:This study revealed AD-associated systemic dysregulation of nutrient sensing and oxidation and CNS-specific alterations in the neuroactive tryptophan pathway and (phospho)creatine degradation. The specific association of amino acids and tryptophan catabolites with AD CSF biomarkers suggests a close relationship with core AD pathology. Our findings warrant validation in independent, larger cohort studies as well as further investigation of factors such as gender and APOE genotype, as well as of other groups, such as preclinical AD, to identify metabolic alterations as potential intervention targets.

Dataset Information

Novel forms of neurofascin 155 in the central nervous system: alterations in paranodal disruption models and multiple sclerosis.

Publications

Novel forms of neurofascin 155 in the central nervous system: alterations in paranodal disruption models and multiple sclerosis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets