Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0040822 (tremor)
 18,428 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Circumstantial and experimental evidence has implicated the immune cytokine interferon-gamma (IFN-gamma) as a key mediator in the pathological changes that are observed in many demyelinating disorders, including the most common human demyelinating disease, multiple sclerosis. To produce an animal model with which to study the effects of IFN-gamma on the CNS, we have generated transgenic mice in which the expression of IFN-gamma has been placed under the transcriptional control of the myelin basic protein (MBP) gene. Transgenic mice generated with this construct have a shaking/shivering phenotype that is similar to that observed in naturally occurring mouse models of hypomyelination (e.g., shiverer, jimpy, quaking), and these transgenic animals have dramatically less CNS myelin than control animals. Reactive gliosis and increased macrophage/microglial F4/80 immunostaining were also observed. Additionally, major histocompatibility complex (MHC) class I and class II mRNA levels were increased in the CNS of MBP/IFN-gamma transgenic mice, and the increase in MHC class I mRNA expression was detected in both white and gray matter regions. Furthermore, cerebellar granule cell migration was abnormal in these animals. These results strongly support the hypothesis that IFN-gamma is a key effector molecule in immune-mediated demyelinating disorders and indicate that the presence of this cytokine in the CNS may also disrupt the developing nervous system.
 ...
PMID:Targeted CNS expression of interferon-gamma in transgenic mice leads to hypomyelination, reactive gliosis, and abnormal cerebellar development. 881 62

Multiple sclerosis (MS) is characterized by inflammatory demyelination of axons and neurodegeneration, the latter inadequately modeled in experimental autoimmune encephalomyelitis (EAE). Susceptibility of inbred mouse strains to EAE is in part determined by major histocompatibility complex haplotype; however, other molecular mechanisms remain elusive. Galectins bind GlcNAc-branched N-glycans attached to surface glycoproteins, forming a molecular lattice that restricts lateral movement and endocytosis of glycoproteins. GlcNAc branching negatively regulates T cell activity and autoimmunity, and when absent in neurons, induces apoptosis in vivo in young adult mice. We find that EAE susceptible mouse strains PL/J, SJL, and NOD have reduced GlcNAc branching. PL/J mice display the lowest levels, partial deficiencies in N-acetylglucosaminyltransferase I, II, and V (i.e. Mgat1, -2, and -5), T cell hyperactivity and spontaneous late onset inflammatory demyelination and neurodegeneration; phenotypes markedly enhanced by Mgat5(+/-) and Mgat5(-/-) backgrounds in a gene dose-dependent manner. Spontaneous disease is transferable and characterized by progressive paralysis, tremor, dystonia, neuronophagia, and axonal damage in both demyelinated lesions and normal white matter, phenocopying progressive MS. Our data identify hypomorphic Golgi processing as an inherited trait that determines susceptibility to EAE, provides a unique spontaneous model of MS, and suggests GlcNAc-branching deficiency may promote T cell-mediated demyelination and neurodegeneration in MS.
 ...
PMID:N-glycan processing deficiency promotes spontaneous inflammatory demyelination and neurodegeneration. 1785 38

Microglia are implicated in both neuroprotection and neurodegeneration, and are a key area of interest with respect to various CNS diseases. Until now, primary microglia prepared by various isolation methods have been widely used to investigate their role in CNS diseases. However, there are some problems with the current isolation methods, such as the numbers of animals required in order to obtain sufficient numbers of microglial cells due to low yields, and also the long periods of culture required. We herein describe a simple, high-yield method for isolating not only primary microglia, but also immortalized microglial cells. Our method allows for the isolation of an almost pure population of microglia with only two steps. First, a primary mixed neural culture was prepared from the brains of 3-day-old postnatal rats. Next, primary microglia were collected for 2 h by adhesion to Aclar plastic film. The average yield by this method was approximately 50 times higher than that of the conventional shaking method. Immortalized microglial cells could also be prepared based on this procedure. A plasmid vector encoding the SV40 large T antigen was transfected into the mixed neural culture using a calcium phosphate precipitation method. Then, proliferating immortalized microglia were collected after several weeks in a similar fashion. Several clones were obtained by limited dilution and one of the immortalized cell lines was designated SMK. The SMK cells exhibited markers specific for the microglia lineage, including Iba-1, CD11b, CD45, CD68, major histocompatibility complex (MHC) class I and MHC class II, but not for the astrocyte-specific markers, GFAP and glutamate aspartate transporter. SMK also showed phagocytic activity. In conclusion, this method resulted in a high-yield preparation of microglial cultures with ease and reproducibility.
 ...
PMID:A simple and high-yield method for preparation of rat microglial cultures utilizing Aclar plastic film. 2109 60

Parkinson's disease (PD) is the second most common form of neurodegeneration in the elderly population. Clinically, it is characterized by tremor, rigidity, slowness of movement, and postural imbalance. A significant association between low serum vitamin D and PD has been demonstrated, suggesting that elevated vitamin D levels might provide protection against PD. Genetic studies have helped identify a number of proteins linking vitamin D to PD pathology, including the major histocompatibility complex (MHC) class II, the vitamin D receptor (VDR), cytochrome P450 2D6 (CYP2D6), chromosome 22, the renin-angiotensin system (RAS), heme oxygenase-1 (HO-1), poly(ADP-ribose) polymerase-1 gene (PARP-1), neurotrophic factor (NTF), and Sp1 transcription factor. Vitamin D has also been implicated in PD through its effects on L-type voltage-sensitive calcium channels (L-VSCC), nerve growth factor (NGF), matrix metalloproteinases (MMPs), prostaglandins (PGs) and cyclooxygenase-2 (COX-2), reactive oxygen species (ROS), and nitric oxide synthase (NOS). A growing body of evidence suggests that vitamin D supplementation may be beneficial for PD patients. Among the different forms of vitamin D, calcitriol (1,25-dihydroxyvitamin D(3)) is best indicated for PD, because it is a highly active vitamin D(3) metabolite with an appropriate receptor in the central nervous system (CNS).
 ...
PMID:Role of vitamin d in Parkinson's disease. 2261 34