Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Borna disease virus (BDV) can induce neurological disease in animals. Since viral nucleic acid, infectious particles and antibodies recognizing BDV antigens were found at higher frequencies in psychiatric patients than in healthy controls, BDV is suspected to cause psychiatric disorders in humans. However, the human origin of these viruses has recently been questioned. To diagnose BDV infections, sera are usually analyzed for antiviral antibodies by indirect immunofluorescence (IFA) on virus-infected cells. This study reveals that the reactive antibodies in human sera mainly recognized the BDV phosphoprotein, whereas animal sera preferentially detected the viral nucleoprotein. Immunoglobulin (Ig) G in sera of experimentally or naturally infected animals bound to the viral antigen with high avidity, ie resisting 3 M urea, whereas reactive IgG in human sera did not. Longitudinal studies showed that reactive human antibodies persisted for many years without gaining high avidity for BDV antigens, indicating that they were probably not induced by BDV but rather by infection with an antigenically related microorganism of unknown identity or by exposure to other related immunogens.
Mol Psychiatry 2001 May
PMID:Low avidity of human serum antibodies for Borna disease virus antigens questions their diagnostic value. 1132 4

Gamma aminobutyric acid (GABA) is a major inhibitory neurotransmitter. Because of its importance and diverse functions, studies of single nucleotide polymorphisms in the GABA receptor genes are of great significance, which may produce useful molecular markers for genetic analysis of neurological disease, and possibly lead to the discovery of pathogenic mutations. We identified eleven SNPs in the entire exon regions, immediate intron regions and promoter region of human GABA receptor gamma2 gene by direct sequencing. In this discovery, 2 non-synonymous cSNPs and 1 splicing variant are found.
Int J Mol Med 2001 Aug
PMID:Identification of SNPs in human gamma aminobutyric acid A receptor gamma2 gene. 1144 76

Parkinson's disease is a progressive neurological disease caused by rather selective degeneration of the dopaminergic neurons in the substantia nigra. Though subject to intensive research, the etiology of this nigral loss is still undetermined and treatment is basically symptomatic. The current major hypothesis is that nigral neuronal death in PD is due to excessive oxidative stress generated by auto and enzymatic oxidation of the endogenous neurotransmitter dopamine (DA), the formation of neuromelanin (NM) and the presence of a high concentration of iron. In this review article although we concisely describe the effects of NM and iron on neuronal survival, we mainly focus on the molecular mechanisms of DA-induced apoptosis. DA exerts its toxic effects through its oxidative metabolites either in vitro or in vivo The oxidative metabolites then activate a very intricate web of signals, which culminate in cell death. The signal transduction pathways and genes, which are associated with DA toxicity are described in detail.
Cell Mol Neurobiol 2001 Jun
PMID:Is there a rationale for neuroprotection against dopamine toxicity in Parkinson's disease? 1156 35

In this report it is demonstrated for the first time that rabies-G envelope of the rabies virus is sufficient to confer retrograde axonal transport to a heterologous virus/vector. After delivery of rabies-G pseudotyped equine infectious anaemia virus (EIAV) based vectors encoding a marker gene to the rat striatum, neurons in regions distal from but projecting to the injection site, such as the dopaminergic neurons of the substantia nigra pars compacta, become transduced. This retrograde transport to appropriate distal neurons was also demonstrated after delivery to substantia nigra, hippocampus and spinal cord and did not occur when vesicular stomatitis virus glycoprotein (VSV-G) pseudotyped vectors were delivered to these sites. In addition, peripheral administration of rabies-G pseudotyped vectors to the rat gastrocnemius muscle leads to gene transfer in motoneurons of lumbar spinal cord. In contrast the same vector pseudotyped with VSV-G transduced muscle cells surrounding the injection site, but did not result in expression in any cells in the spinal cord. Long-term expression was observed after gene transfer in the nervous system and a minimal immune response which, together with the possibility of non-invasive administration, greatly extends the utility of lentiviral vectors for gene therapy of human neurological disease.
Hum Mol Genet 2001 Sep 15
PMID:Rabies virus glycoprotein pseudotyping of lentiviral vectors enables retrograde axonal transport and access to the nervous system after peripheral delivery. 1159 Jan 28

Huntingtin is an essential protein that with mutant polyglutamine tracts initiates dominant striatal neurodegeneration in Huntington's disease (HD). To assess the consequences of mutant protein when huntingtin is limiting, we have studied three lines of compound heterozygous mice in which both copies of the HD gene homolog (Hdh) were altered, resulting in greatly reduced levels of huntingtin with a normal human polyglutamine length (Q20) and/or an expanded disease-associated segment (Q111): Hdh(neoQ20)/Hdh(neoQ20), Hdh(neoQ20)/Hdh(null) and Hdh(neoQ20)/Hdh(neoQ111). All surviving mice in each of the three lines were small from birth, and had variable movement abnormalities. Magnetic resonance micro-imaging and histological evaluation showed enlarged ventricles in approximately 50% of the Hdh(neoQ20)/Hdh(neoQ111) and Hdh(neoQ20)/Hdh(null) mice, revealing a developmental defect that does not worsen with age. Only Hdh(neoQ20)/Hdh(neoQ111) mice exhibited a rapidly progressive movement disorder that, in the absence of striatal pathology, begins with hind-limb clasping during tail suspension and tail stiffness during walking by 3-4 months of age, and then progresses to paralysis of the limbs and tail, hypokinesis and premature death, usually by 12 months of age. Thus, dramatically reduced huntingtin levels fail to support normal development in mice, resulting in reduced body size, movement abnormalities and a variable increase in ventricle volume. On this sensitized background, mutant huntingtin causes a rapid neurological disease, distinct from the HD-pathogenic process. These results raise the possibility that therapeutic elimination of huntingtin in HD patients could lead to unintended neurological, as well as developmental side-effects.
Hum Mol Genet 2001 Oct 15
PMID:The HD mutation causes progressive lethal neurological disease in mice expressing reduced levels of huntingtin. 1170 39

Mutations in the L1CAM gene cause a highly variable neurological disease described as X-linked hydrocephalus, MASA syndrome or spastic paraplegia type I. Over one-third of the mutations identified in affected boys are missense, unique to individual families and distributed primarily across the large extracellular domain of the L1 protein. We have examined the effects of 25 missense mutations on binding to homophilic (L1) and heterophilic (TAX-1) ligands as well as on intracellular trafficking. All but three of these result in reduced ligand binding or impaired movement to the surface of COS and CHO cells. Therefore, we demonstrate for the first time that most missense mutations found in affected families have functional consequences. Furthermore, mutations that are predicted to affect the structure of individual extracellular domains are more likely to affect intracellular processing and/or ligand binding than those mutations affecting surface properties of the molecule.
Hum Mol Genet 2002 Jan 01
PMID:Disease-associated mutations in L1 CAM interfere with ligand interactions and cell-surface expression. 1177 94

Mucopolysaccharidosis (MPS) IIIB is characterized by mild somatic features and severe neurological diseases leading to premature death. No definite treatment is available for MPS IIIB patients. We constructed two recombinant adeno-associated virus (rAAV) vectors containing the human alpha-N-acetylglucosaminidase (NaGlu) cDNA driven by either a CMV or a neuron-specific enolase (NSE) promoter. In vitro, these rAAV vectors mediated efficient expression of recombinant NaGlu in human MPS IIIB fibroblasts and mouse MPS IIIB somatic and brain primary cell cultures. The secreted rNaGlu was taken up by both human and mouse MPS IIIB cells in culture and degraded the accumulated glycosaminoglycans (GAG). A direct microinjection (10(7) viral particles, 1 microl/10 minutes per injection) of vectors containing the NSE promoter resulted in long-term (6 months, the duration of the experiments) expression of rNaGlu in multiple brain structures/areas of adult MPS IIIB mice. Consistent with previous studies, the main target cells were neurons. However, while vector typically transduced an area of 400-500 microm surrounding the infusion sites, the correction of GAG storage involved neurons of a much broader area (1.5 mm) in a 6-month duration of experiments. These results provide a basis for the development of a treatment for neurological disease in MPS IIIB patients using AAV vectors.
Mol Ther 2002 Jan
PMID:Neurological correction of lysosomal storage in a mucopolysaccharidosis IIIB mouse model by adeno-associated virus-mediated gene delivery. 1178 44

Niemann-Pick type C disease is a progressive neurological disease with cholesterol storage in liver, and npc1-/- mice share these features and are sterile. We have searched for the cause of sterility and found normal folliculogenesis and progesterone levels but lack of implantation. Multiple drug resistance (MDR) P-glycoproteins are plasma membrane proteins implicated in the movement of drugs and lipids across membranes. Their functions are inhibited by progesterone, which has been shown to alter cellular cholesterol homeostasis and has implicated P-glycoproteins in the movement of cholesterol to the endoplasmic reticulum. We have introduced the mdr1a knockout into the npc1 mutant line. While the neurological disease continues at its usual rate, preventing the females from taking care of their litters, npc1-/-, mdr1a-/- females became fertile. Although the mdr1a P-glycoprotein co-localizes with caveolae, neither caveolin-1 nor npc1 levels were significantly altered in the livers of double homozygotes. The absence of mdr1a was confirmed by immunoblotting, but npc1 deficiency was not associated with consistent changes in cerebellar mdr1a in mdr1a+/+ mice. The results show that a mdr1a mutation is an in vivo suppressor of female sterility in npc1 deficient mice.
Mol Reprod Dev 2002 Jun
PMID:mdr1a deficiency corrects sterility in Niemann-Pick C1 protein deficient female mice. 1198 26

Recent studies have implicated chronic elevated exposures to environmental agents, such as metals (e.g. manganese, Mn) and pesticides, as contributors to neurological disease. Eighteen-month-old rats received intraperitoneal injections of manganese chloride (6 mg Mn/kg/day) or equal volume of saline for 30 days in order to study the effect of manganese on the dopamine- and GABA-neurons. The structures studied were substantia nigra, striatum, ventral tegmental area, nucleus accumbens and globus pallidus. First, we studied the enzymatic activity of mitochondrial complex II succinate dehydrogenase (SDH). We found an overall decrease of SDH in the different brain areas analyzed. We then studied the mRNA levels for tyrosine hydroxylase (TH) and the dopamine transporter (DAT) by in situ hybridization. TH mRNA but not DAT mRNA was significantly induced in substantia nigra and ventral tegmental area following Mn treatment. Correspondingly, TH immunoreactivity was increased in substantia nigra and ventral tegmental area. Manganese treatment significantly decreased GAD mRNA levels in individual GABAergic neurons in globus pallidus but not in striatum. We also quantified the density of glial fibrillary acidic protein (GFAP)-labeled astrocytes and OX-42 positive cells. Reactive gliosis in response to Mn treatment occurred only in striatum and substantia nigra and the morphology of the astrocytes was different than in control animals. These results suggest that the nigrostriatal system could be specifically damaged by manganese toxicity. Thus, changes produced by manganese treatment on 18-month-old rats could play a role in the etiology of Parkinson's disease.
Brain Res Mol Brain Res 2002 Jun 30
PMID:Differential regulation of glutamic acid decarboxylase mRNA and tyrosine hydroxylase mRNA expression in the aged manganese-treated rats. 1210 97

Mucolipidosis Type IV (MLIV) is a lysosomal storage disorder that is characterized by severe neurologic and ophthalmologic abnormalities. It is a progressive disease that usually presents during the first year of life with mental retardation, corneal opacities, and delayed motor milestones. First described in 1974, MLIV is a rare autosomal recessive disease and the majority of patients diagnosed to date are of Ashkenazi Jewish descent. MLIV was originally classified as a lysosomal storage disorder due to the abnormal accumulation of mucopolysaccharides and lipids. Extensive studies in MLIV cells, however, have shown that the abnormal storage is due to a defect in the late endocytic pathway. Positional cloning led to the recent discovery of a novel gene on human chromosome 19, MCOLN1, that is mutated in MLIV. To date 14 independent mutations have been reported in MCOLN1, with two mutations accounting for 95% of the Ashkenazi Jewish MLIV alleles. The identification of the MLIV gene has led to a simple tool for definitive diagnosis and will permit carrier screening in the Ashkenazi Jewish population. MCOLN1 is a new member of the transient receptor potential (TRP) cation channel gene family. The protein encoded by MCOLN1, mucolipin-1, has six predicted transmembrane domains and a putative channel pore. The identification of mutations in MCOLN1 represents the first example of a neurological disease caused by a TRP-related channel. While the function of mucolipin-1 is currently unknown, homology to the TRP superfamily and the recent description of the C. elegans mucolipin-1 homolog allow us to begin to speculate about the role of mucolipin-1 in diverse cellular processes.
Curr Mol Med 2002 Aug
PMID:The molecular basis of mucolipidosis type IV. 1212 10


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