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Biomedical subjects

Alastair Compston

Publications and source records attributed to Alastair Compston.

9 recordsLinked to original sources
PubMed2003

Oligodendrocytes promote neuronal survival and axonal length by distinct intracellular mechanisms: a novel role for oligodendrocyte-derived glial cell line-derived neurotrophic factor.

Interactions of CNS cells lead to the establishment of complex neural systems. Specifically, oligodendrocytes form myelin sheaths around axons that enable rapid electrical conduction of impulses. Recent evidence has emerged that oligodendrocytes may also release trophic factors promoting neuronal survival. We therefore studied the effects of factors released from cells of the oligodendrocyte lineage on neuronal survival and also on the morphology of neurons. Neurons derived from rat embryonic cortices were cultured and exposed to media conditioned by oligodendrocyte precursor cells (OPCs) or differentiated oligodendrocytes. In line with previous studies, exposure of OPC and oligodendrocyte-conditioned media (OCM) increased survival, a phosphatidylinositol 3'-kinase (PI3kinase)/Akt-dependent phenomenon. In addition, exposure of neurons to OCM but not OPC conditioned media resulted in increased axonal length per neuron, as detected by antibodies to phosphorylated neurofilaments. OCM exposure resulted in activation of the MAPkinase/extracellular signal-regulated kinase pathway, inhibition of which significantly reduced oligodendrocyte-mediated enhancement of axonal length but, unlike PI3kinase inhibition, had no effect on neuronal survival. Furthermore, we identify glial cell line-derived neurotrophic factor (GDNF) production by differentiated oligodendrocytes and provide evidence that implicates GDNF in OCM-mediated axonal effects, independent of its effect on neuronal survival. Therefore, we have shown that factors released by OPCs and oligodendrocytes induce the activation of distinct intracellular pathways within neurons, which have different functional effects on the cell.

Animals↗
PubMed2003

Oligodendroglial-derived stress signals recruit microglia in vitro.

Rat oligodendrocytes cultured without the essential survival factors serum and insulin die over a 48 h period. Analysis of supernatants from these dying cultures reveals a microglial chemokine released in advance of significant cell death. The observed microglial chemotactic effect is dose-dependent and not due to release of cellular debris. Interferon (IFN)-gamma activated microglia are more sensitive to the microglial chemokine. We show in co-culture that recruited non-activated microglia can enhance oligodendroglial survival whereas IFN-gamma activation of microglia induces contact-dependent oligodendroglial death. Thus, whilst the initial recruitment of microglia by stressed oligodendroglia may represent part of a survival process engaged by injured cells, this does not necessarily ensure survival.

Animals↗
PubMed2002

A genome screen for linkage disequilibrium in HLA-DRB1*15-positive Germans with multiple sclerosis based on 4666 microsatellite markers.

Multiple sclerosis (MS) is a demyelinating disorder of the central nervous system with putative autoimmune aetiology and complex genetic background. Here, we report the results of a genome screen for linkage disequilibrium (LD) by using 6000 microsatellite markers in 198 HLA-DRB1*15-positive MS patients and 198 unrelated controls (pooled DNA); 4666 analysed markers could be included in the resulting association map, from which 87 revealed significant differences between MS cases and controls.

Adult↗
PubMed2002

Multiple sclerosis.

Multiple sclerosis is the prototype inflammatory autoimmune disorder of the central nervous system and, with a lifetime risk of one in 400, potentially the most common cause of neurological disability in young adults. As with all complex traits, the disorder results from an interplay between as yet unidentified environmental factors and susceptibility genes. Together, these factors trigger a cascade of events, involving engagement of the immune system, acute inflammatory injury of axons and glia, recovery of function and structural repair, post-inflammatory gliosis, and neurodegeneration. The sequential involvement of these processes underlies the clinical course characterised by episodes with recovery, episodes leaving persistent deficits, and secondary progression. The aim of treatment is to reduce the frequency, and limit the lasting effects, of relapses, relieve symptoms, prevent disability arising from disease progression, and promote tissue repair. Despite limited success in each of these categories, everyone touched by multiple sclerosis looks for a better dividend from applying an improved understanding of the pathogenesis to clinical management.

Adult↗
PubMed2002

Genetic analysis of multiple sclerosis.

The increased recurrence risk within families indicates a role for genetic factors in the etiology of multiple sclerosis. Genes may influence susceptibility to the development of multiple sclerosis and the subsequent course of the disease. To date, associations have only been demonstrated consistently with class II major histocompatibility complex (MHC) alleles. The relatively low yield from additional candidate gene studies is only modestly advanced by several whole-genome linkage analyses, and by the first in a series of planned whole-genome linkage disequilibrium screens for allelic associations. The aims of linkage and association are to narrow the search for chromosomal regions encoding genes for multiple sclerosis and, with information from the human gene project, suggest new positional candidates. In time, it is expected that these genes will include some that confer susceptibility to the general process of autoimmunity, others that are specific for multiple sclerosis in all populations, some that act only in defined ethic groups, and those that determine particular phenotypes or shape the clinical course. These genetic analyses are predicated on the assumption that multiple sclerosis is one disease; a major part of future studies will be to resolve the question of disease heterogeneity in multiple sclerosis. When eventually in place, the potential of this genetic knowledge for improved understanding of the pathogenesis of multiple sclerosis and designing novel treatments is considerable.

DNA Mutational Analysis↗
PubMed2002

Different pathways for iNOS-mediated toxicity in vitro dependent on neuronal maturation and NMDA receptor expression.

Co-localization of activated microglia and damaged neurones seen in brain injury suggests microglia-induced neurodegeneration. Activated microglia release two potential neurotoxins, excitatory amino acids and nitric oxide (NO), but their contribution to mechanisms of injury is poorly understood. Using co-cultures of rat microglia and embryonic cortical neurones, we show that inducible NO synthase (iNOS)-derived NO aloneis responsible for neuronal death from interferon gamma (IFNgamma) +lipopolysaccharide (LPS)-activated microglia. Neurones remain sensitive to NO irrespective of maturation state but, whereas blocking NMDA receptor activation with MK801 has no effect on NO-mediated toxicity to immature neurones, MK801 rescues 60-70% of neurones matured in culture for 12 days. Neuronal expression of NMDA receptors increases with maturation in culture, accounting for increased susceptibility to excitotoxins seen in more mature cultures. We show that MK801 delays the death of more mature neurones caused by the NO-donor DETA/NO indicating that NO elicits an excitotoxic mechanism, most likely through neuronal glutamate release. Thus, similar concentrations of nitric oxide cause neuronal death by two distinct mechanisms: NO acts directly upon immature neurones but indirectly, via NMDA receptors, on more mature neurones. Our results therefore extend existing evidence for NO-mediated toxicity and show a complex interaction between inflammatory and excitotoxic mechanisms of injury in mature neurones.

Animals↗
PubMed2002

A whole genome screen for linkage disequilibrium in multiple sclerosis confirms disease associations with regions previously linked to susceptibility.

Linkage analysis in multiplex families has provisionally identified several genomic regions where genes influencing susceptibility to multiple sclerosis are likely to be located. It is anticipated that association mapping will provide a higher degree of resolution, but this more powerful approach is limited by the substantial genotyping effort required. Here, we describe the first use of DNA pooling to screen the whole genome for association in multiple sclerosis based on a 0.5 cM map of microsatellite markers and using four DNA pools derived from cases (n = 216), controls (n = 219) and trio families (n = 745 affected individuals and their 1490 parents). The 10 markers showing the greatest evidence for association with multiple sclerosis that emerge from this analysis include three from the HLA region on chromosome 6p (D6S1615, D6S2444 and TNFa), providing a positive control for the method, four from regions previously identified by linkage analysis in UK multiplex families (two mapping to chromosome 17q GCT6E11 and D17S1535; one to chromosome 1p GGAA30B06; and one to 19q D19S585), and three from novel sites with respect to linkage analysis (D1S1590 at 1q; D2S2739 at 2p; and D4S416 at 4q). Our results thus provide further supporting evidence for the candidature of 6p, 17q, 19q and 1p as regions encoding susceptibililty genes for multiple sclerosis. The protocol used in this UK-based study is now being extended to 18 additional sites in Europe in order to search for susceptibility genes shared between populations of common ancestry, as well as those that exert ethnically more restricted effects.

Adult↗