The role of complex gangliosides in glial cell biology

Gangliosides are a family of sialic acid-containing glycosphingolipids that are enriched in the nervous system. They are located in the outer leaflet of the plasma membrane within lipid rafts and are thought to be involved in numerous cellular events, including proliferation, differentiation, migration and neurite outgrowth. Gangliosides have also been shown to have neuroprotective actions and have been considered as candidates for the treatment of several neurodegenerative disorders. In this thesis, the role of gangliosides in glial proliferation, migration and differentiation as well as the regeneration of the olfactory system and myelination were studied using mice lacking enzymes involved in ganglioside biosynthesis. Regeneration of the olfactory system in ganglioside knockout mice was similar to that of wild-type mice. However, proliferation of olfactory ensheathing cells grown on collagen and the migration of Schwann cells grown on laminin or collagen was increased in Sia T -/- mice, which lack b-series gangliosides but have increased levels of a-series gangliosides. These findings suggest that complex gangliosides modulate glial cell function to some extent. However, since the effects observed were subtle, it is possible that simpler gangliosides are able to compensate for the lack of complex gangliosides. Axonal density and myelination were unaffected in ganglioside knockout mice. However, the localisation of sodium channels at the node of Ranvier and potassium channels at juxtaparanode was retarded in GalNAc T -/- mice lacking all complex gangliosides, suggesting that complex gangliosides modulate the formation of nodes of Ranvier. In addition, GalNAc T -/- mice had significantly lower numbers of NG2 positive early oligodendrocyte progenitors compared to wild-type and Sia T -/- mice, suggesting that complex gangliosides may affect early progenitor differentiation, proliferation or survival

No diagnostic value of plasma clusterin in Alzheimer's disease.

There is an urgent need for biomarkers to enable early diagnosis of Alzheimer's disease (AD). It has recently been shown that a variant within the clusterin gene is associated with increased risk of AD and plasma levels of clusterin have been found to be associated with the risk of AD. We, therefore, investigated the diagnostic value of clusterin by quantifying clusterin using an ELISA in plasma from 171 controls, 127 patients with AD, 82 patients with other dementias and 30 patients with depression. We observed similar plasma clusterin levels in controls, AD patients and patients with other dementias, suggesting that plasma clusterin levels have no diagnostic value for AD. There was a slight, but significant, increase in plasma clusterin in patients with depression compared to all other groups tested, which may warrant further investigation

Analysis of White Adipose Tissue Gene Expression Reveals CREB1 Pathway Altered in Huntington's Disease.

In addition to classical neurological symptoms, Huntington's disease (HD) is complicated by peripheral pathology and both the mutant gene and the protein are found in cells and tissues throughout the body. Despite the adipose tissue gene expression alterations described in HD mouse models, adipose tissue and its gene expression signature have not been previously explored in human HD

A critical evaluation of wet biomarkers for huntington's disease : Current status and ways forward

There is an unmet clinical need for objective biomarkers to monitor disease progression and treatment response in Huntington's disease (HD). The aim of this review is, therefore, to provide practical advice for biomarker discovery and to summarise studies on biofluid markers for HD. A PubMed search was performed to review literature with regard to candidate saliva, urine, blood and cerebrospinal fluid biomarkers for HD. Information has been organised into tables to allow a pragmatic approach to the discussion of the evidence and generation of practical recommendations for future studies. Many of the markers published converge on metabolic and inflammatory pathways, although changes in other analytes representing antioxidant and growth factor pathways have also been found. The most promising markers reflect neuronal and glial degeneration, particularly neurofilament light chain. International collaboration to standardise assays and study protocols, as well as to recruit sufficiently large cohorts, will facilitate future biomarker discovery and development

Antibodies against phosphorylcholine are not altered in plasma of patients with Alzheimer's disease

Background: Phosphorylcholine is one of the major epitopes of oxidised low density lipoprotein. Low levels of IgM antibodies against phosphorylcholine (anti-PC) are associated with development of myocardial infarction and stroke. It has been shown that patients with Alzheimer's disease and other dementias have significantly lower serum anti-PC levels compared to controls, suggesting that low levels of atheroprotective anti-PC may play a role in AD and dementia. Methods: We quantified levels of anti-PC levels using an ELISA in plasma from 176 controls, 125 patients with Alzheimer's disease, 19 patients with vascular dementia and 63 patients with other dementias. Results: We observed similar plasma anti-PC levels in controls, patients with Alzheimer's disease, and other dementias. Conclusions: Our data suggests that anti-PC is not useful as a biomarker for Alzheimer's disease

Development of novel mass spectrometry methodology to detect post-translational modifications in oxidative stress and disease

This paper presented at the European Meeting of the Society-for-Free-Radical-Research-Europe 2007, discusses the development of novel mass spectrometry methodology to detect post-translational modifications in oxidative stress and disease

Flt3 ligand does not differentiate between Parkinsonian disorders.

Differential diagnosis of parkinsonian disorders is challenging because of overlapping symptoms, especially during early stages of disease. No validated biomarkers are available for early and accurate diagnosis of multiple system atrophy and other parkinsonian disorders. It has been reported that flt3 ligand levels in cerebrospinal fluid could clearly differentiate patients with Parkinson's disease from patients with multiple system atrophy, with 99% sensitivity and 95% specificity

Skeletal muscle atrophy in r6/2 mice - altered circulating skeletal muscle markers and gene expression profile changes.

In addition to classical neurological symptoms, Huntington's disease (HD) is complicated by peripheral pathology, including progressive skeletal muscle wasting, and common skeletal muscle gene expression changes have been shown in HD mice and human HD

A porous silicon immunoassay platform for fluorometric determination of alpha-synuclein in human cerebrospinal fluid

Levels of total and/or oligomeric alpha-synuclein may be used as a biomarker tool to aid in the diagnosis and development of new disease-modifying therapies. We report here on a porous silicon antibody microarray for the fluorimetric determination of cerebrospinal fluid levels of total alpha-synuclein, a protein involved the pathology of Parkinson's disease. The surface of porous silicon has a 3-dimensional macro- and nanoporous structure, and this offers a large binding capacity for capturing probe molecules. Porous silicon also warrants efficient immobilization of antibodies by surface adsorption, and does not require chemical immobilization. The platform requires 10 mu L of cerebrospinal fluid, and each test requires 4 h for assay only (including immobilization of capturing antibody). The limit of detection is 35 pg mL(-1) of alpha-synuclein in cerebrospinal fluid, and the dynamic analytical range extends from 0.01 to 100 ng center dot mL(-1)

Generation of functioning nephrons by implanting human pluripotent stem cell-derived kidney progenitors.

Human pluripotent stem cells (hPSCs) hold great promise for understanding kidney development and disease. We reproducibly differentiated three genetically distinct wild-type hPSC lines to kidney precursors that underwent rudimentary morphogenesis in vitro. They expressed nephron and collecting duct lineage marker genes, several of which are mutated in human kidney disease. Lentiviral-transduced hPSCs expressing reporter genes differentiated similarly to controls in vitro. Kidney progenitors were subcutaneously implanted into immunodeficient mice. By 12 weeks, they formed organ-like masses detectable by bioluminescence imaging. Implants included perfused glomeruli containing human capillaries, podocytes with regions of mature basement membrane, and mesangial cells. After intravenous injection of fluorescent low-molecular-weight dextran, signal was detected in tubules, demonstrating uptake from glomerular filtrate. Thus, we have developed methods to trace hPSC-derived kidney precursors that formed functioning nephrons in vivo. These advances beyond in vitro culture are critical steps toward using hPSCs to model and treat kidney diseases