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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neuronal cell death occurs during development of the central nervous system as well as in pathological situations such as acute injury and progressive degenerative diseases. For instance, granule cells in the developing cerebellum and neuronal precursor cells in the cortex undergo programmed cell death, or apoptosis. There is currently strong debate conceming the mechanism of death in many degenerative events such as ischemia, blunt head trauma, excitotoxicity and neurodegenerative diseases, i.e. Alzheimer's disease. Neurons can die a necrotic death when the initial insult is too great; apoptosis requires "planning." For example, the cell death seen in the core of an ischemic infarct is necrotic, while in the surrounding penumbra region the death is probably apoptotic. Regardless of the degenerative pathway, damaged or dead neurons are a hallmark of many diseases including Alzheimer's, Parkinson's, glaucoma, ischemia and multiple sclerosis. Molecules such as cytokines, chemokines, reactive nitrogen/oxygen species, and proteases play an important role in promoting and/or mediating neurodegeneration. Proteases have been implicated in both physiological and pathological events, suggesting their intervention in key points when things go awry. In this review we will summarize recent findings linking extracellular proteases with neuronal cell death in both human diseases and their animal models.
Cell Mol Biol (Noisy-le-grand) 2002 Mar
PMID:Extracellular proteases and neuronal cell death. 1199 Apr 50

We recently found that cerebrospinal fluid (CSF) from multiple sclerosis (MS) patients contains a gliotoxic activity which induces programmed cell death of astrocytes and oligodendrocytes and could be the main contributing factor to the massive glial cell death seen in MS active lesions. A previous clinical study aimed at evaluating the gliotoxicity of CSF from a cohort of MS patients from France indicated that MS patients with the active form of the disease do indeed present significant CSF gliotoxicity. To extend this observation, the effect of 141 CSFs from United States patients with different neurological diseases (including 71 MS) was tested on immortalized astrocytes. A cell death assay showed that a gliotoxic activity is significantly present in the CSF from MS patients with the active forms. Thus, this gliotoxic activity may represent a critical pathogenic factor in the neuropathology of active MS by playing a role both in demyelinisation and alteration of the blood-brain barrier.
Cell Mol Biol (Noisy-le-grand) 2002 Mar
PMID:Association of a gliotoxic activity with active multiple sclerosis in US patients. 1199 Apr 56

The cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients contains a 17 kDa glycoproteic factor with gliotoxic properties in vitro. In order to study the physiopathological role of this gliotoxic factor in vivo, we have injected a partially purified preparation and appropriate controls in rat CSF and investigated whether it induces cell death in the rat central nervous system (CNS), 10 days and 3 months after injection. We used the TUNEL assay in association with specific immunohistochemistry to characterize dying cells in the gliotoxic factor- treated rat CNS. At 10 days post-injection, TUNEL-positive cells were observed in the whole rat CNS. They were particularly numerous in the choroid plexus, ependymal epithelium, cerebral white matter, cerebral vascular endothelium, arachnoid spaces and less frequent in the gray matter of brain and spinal cord. The predominant type of TUNEL-positive cells observed at 10 days post-injection was astrocytes, in white matter, gray matter, occasionnally around damaged endothelial cells in periventricular and subpial spaces. Other TUNEL-positive cells were identified as oligodendrocytes by an oligodendrocyte specific RIP immunostaining, at 10 days post-treatment with the gliotoxic factor. Interestingly, demyelination and death of oligodendrocytes were more important 3 months post-injection: TUNEL-RIP positive oligodendrocytes were generally associated with multifocal demyelinating areas. Clearly, the 17 kDa gliotoxic factor injection in rat CSF triggers demyelination and may be used as a new animal model for MS. Also, our results suggest a new possible scenario for MS pathogenesis: death of oligodendrocytes and astrocytes, stimulated by the MS gliotoxic factor causes the breakdown of the blood-brain barrier (BBB) and the demyelinating cascade.
Cell Mol Biol (Noisy-le-grand) 2002 Mar
PMID:Induction of cell death in rat brain by a gliotoxic factor from cerebrospinal fluid in multiple sclerosis. 1199 Apr 57

Aberrant expression of the sensory neuron specific (SNS) sodium channel Na(v)1.8 has been demonstrated in cerebellar Purkinje cells in experimental models of multiple sclerosis (MS) and in human MS. The aberrant expression of Na(v)1.8, which is normally present in primary sensory neurons but not in the CNS, may perturb cerebellar function, but the mechanisms that trigger it are not understood. Because axotomy can provoke changes in Na(v)1.8 expression in dorsal root ganglion (DRG) neurons, we tested the hypothesis that axotomy can provoke an up-regulation of Na(v)1.8 expression in Purkinje cells, using a surgical model that transects axons of Purkinje cells in lobules IIIb-VII in the rat. In situ hybridization and immunocytochemistry did not reveal an up-regulation of Na(v)1.8 mRNA or protein in axotomized Purkinje cells. Hybridization and immunostaining signals for the sodium channel Na(v)1.6 were clearly present, demonstrating that sodium channel transcripts and protein were present in experimental cerebella. These results demonstrate that axotomy does not trigger the expression of Na(v)1.8 in Purkinje cells.
Brain Res Mol Brain Res 2002 May 30
PMID:Axotomy does not up-regulate expression of sodium channel Na(v)1.8 in Purkinje cells. 1200 40

The genetics of multifactorial diseases characterized by autoimmune phenomena are elusive so far. Yet, it is clear that the genetic contribution to a given clinically defined autoimmune disease entity is mostly variable and highly complex. On the basis of two basically different model diseases, Wegener's Granulomatosis and multiple sclerosis, approaches are discussed to unravel at least certain genetic predisposition factors. Major difficulties in these analyses arise from (in)exact definition of the clinical phenotype (disease entity), the vast number of potential candidate genes, the small to modest contribution of each genetic variation to disease risk and the combinatorial possibilities.
Cell Mol Biol (Noisy-le-grand) 2002 May
PMID:On the genetic contribution to selected multifactorial diseases with autoimmune characteristics. 1203 Apr 39

Protective autoimmunity is the body's defense mechanism against destructive self-compounds such as those commonly associated with neurodegenerative disorders. Autoimmune disease and neurodegenerative disorders can thus be viewed as two extreme manifestations of the same process. Therefore, when designing therapy, it is important to avoid an approach that will cure the one by invoking the other. One way to stop, or at least slow down, the progression of neurodegeneration without risking development of an autoimmune disease is by boosting protective autoimmunity in a well-controlled way. Copolymer 1 (Cop-1), an approved drug for the treatment of multiple sclerosis, can be used as a treatment for autoimmune diseases and as a therapeutic vaccine for neurodegenerative diseases. We propose that the protective effect of Cop-1 vaccination is obtained through a well-controlled inflammatory reaction, and that the activity of Cop-1 in driving this reaction derives from its ability to serve as a 'universal antigen' by weakly activating a wide spectrum of self-reactive T cells.
Trends Mol Med 2002 Jul
PMID:Dual action of glatiramer acetate (Cop-1) in the treatment of CNS autoimmune and neurodegenerative disorders. 1211 10

The association of multiple sclerosis (MS) with alleles A and G of the cytotoxic T-lymphocyte antigen 4 (CTLA4) gene, a candidate gene for autoimmune disorders, was studied. The allele polymorphism results from single nucleotide substitution (A/G) in position +49 of exon 1 and leads to substitution Thr-->Ala in the leader peptide. The case-control study involved two groups of ethnic Russians: 168 MS patients and 209 healthy subjects from central Russia. Genotype frequencies were in agreement with the Hardy-Weinberg equilibrium in both groups (P > 0.05). The controls significantly differed in CTLA4 allele and genotype frequencies from Mongoloids but not from other Caucasians. No association was observed between MS and CTLA4. In addition, the combined association with MS was analyzed for both the CTLA4 alleles and allele groups of HLA DRB1. The results showed that the CTLA4 dimorphism does not affect susceptibility to MS in ethnic Russians, be these stratified or not with regard to DRB1 alleles corresponding to serologic specificities DR1 to DR16.
Mol Biol (Mosk)
PMID:[Polymorphism A/G in position +49 of CTLA4 exon 1 in multiple sclerosis in Russians]. 1217 68

It is well established that CD4(+) T cells are of central importance in mediating the autoimmune destruction associated with the neurological demyelinating disease Multiple sclerosis (MS) and the rodent model of MS, EAE (experimental allergic encephalomyelitis). However, other cells also play a critical role in the inflammatory events that lead to the varying degrees of myelin and axonal damage observed in this disease syndrome. In this review, we present evidence that mast cells, best studied in the context of allergic disease, contribute to EAE disease pathology. Using mast cell-deficient mice, we demonstrate that mast cells are necessary for the full manifestation of MOG-induced EAE disease and show that cross-linking of Fc receptors is one mechanism of mast cell activation in disease. In addition, we provide evidence that mast cells exert influences outside the CNS, perhaps through the effects on the generation of the anti-MOG T cell response.
Mol Immunol 2002 Sep
PMID:Mechanisms underlying mast cell influence on EAE disease course. 1221 11

Multiple sclerosis (MS) is a common and frequently disabling autoimmune disorder mediated by autoaggressive T cells and autoantibodies that target central nervous system myelin. While numerous studies have demonstrated a strong genetic component to MS, it has been difficult to identify the specific genes involved. Several genomic screens have been undertaken to locate such genes, but have not provided consistent gene localization, except for the MHC on chromosome 6p21 and a locus on chromosome 19q13. To determine which of the original genomic locations presented in the US genome screen could be replicated, a more detailed analysis of additional families was performed. The results, derived from a population of 266 affected individuals belonging to 98 multiplex families, continue to support linkage to chromosomes 6p21, 6q27, and 19q13 with LOD scores>3.0, and suggest that regions on chromosomes 12q23-24 and 16p13 may also harbor susceptibility loci for MS. Analysis taking into account the known HLA-DR2 association identified two additional potential linkage regions on chromosomes 7q21-22 and 13q33-34. These regions can now be targeted for detailed study to identify the underlying MS susceptibility genes.
Hum Mol Genet 2002 Sep 15
PMID:Multiple susceptibility loci for multiple sclerosis. 1221 53

Genome-wide linkage analyses performed in a Finnish study sample have identified four potential predisposing loci for multiple sclerosis (MS). Here we made an effort to restrict the wide linkage region on chromosome 17 with a dense set of 31 markers using multipoint linkage analyses and monitoring for shared marker alleles in MS chromosomes. We carried out the linkage analyses in 22 Finnish multiplex MS families originating from a regional subisolate that shows an exceptionally high prevalence of MS in order to minimize the genetic and environmental heterogeneity of the study sample. Thirty markers on the 23 cM initial interval gave positive pairwise LOD scores. We monitored for shared haplotypes among affected family members within a family, and identified an approximately 4 cM region flanked by the markers D17S1792 and ATA43A10 in 17 out of the 22 families (77.3%). The multipoint linkage analyses using Genehunter and SIMWALK 2.40 provided further evidence for the same 4 cM region, for example a maximal multipoint NPL score of 5.98 (P<0.0002). We observed nominal evidence for association to MS, with one marker flanking the shared region, and this association was replicated in the additional set of families. Using the combined power of linkage, association and shared haplotype analyses, we were thus able to restrict the MS locus on chromosome 17q from 23 cM to a 4 cM region covering a physical interval of approximately 2.5 Mb. Thus, this study describes the restriction of an MS locus outside the HLA region into a segment approachable by molecular tools.
Hum Mol Genet 2002 Sep 15
PMID:Fine mapping of a multiple sclerosis locus to 2.5 Mb on chromosome 17q22-q24. 1221 54


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