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

Chediak Higashi syndrome (CHS) is a rare, autosomal recessive disorder that affects multiple systems of the body. Patients with CHS exhibit hypopigmentation of the skin, eyes and hair, prolonged bleeding times, easy bruisability, recurrent infections, abnormal NK cell function and peripheral neuropathy. Morbidity results from patients succumbing to frequent bacterial infections or to an "accelerated phase" lymphoproliferation into the major organs of the body. Current treatment for the disorder is bone marrow transplant, which alleviates the immune problems and the accelerated phase, but does not inhibit the development of neurologic disorders that grow increasingly worse with age. There are several animal models of CHS, the beige mouse being the most characterized. Positional cloning and YAC complementation resulted in the identification of the Beige and CHS1/LYST genes. These genes encode a cytosolic protein of 430,000 Da. Sequence analysis identified three conserved regions in the protein: a HEAT repeat motif at the amino-terminus that contains several a helices, a BEACH domain containing the amino acid sequence WIDL, and a WD40 repeat motif, which is described as a protein-protein interaction domain. The presence of the BEACH and WD40 domains defines a family of genes that encode extremely large proteins.
Curr Mol Med 2002 Aug
PMID:Chediak-Higashi syndrome: a clinical and molecular view of a rare lysosomal storage disorder. 1212 12

Gene transfer into the brain allows the manipulation of transgene expression in both time and space. Recently developed gene transfer technologies allow transgenes to be expressed in any anatomically, biochemically or functionally distinct group of brain cells. Gene transfer has been used to alter the expression of neurotransmitter receptors, ion channels, signaling proteins, neuronal growth, differentiation and survival factors, and thus to modify brain anatomy, neuron physiology, behavior and pathology. However, challenges remain in making gene therapy a more widespread tool for the treatment of neurological disease. We have identified the following as areas needing development: access and delivery of viral vectors to the brain; diffusion of viral vectors and transgenes throughout large areas of brain tissue; viral vector side effects and toxicity, inflammatory and immune responses to vectors; long-term stable transgene expression; cell type-specific expression of transgenes; and the ability of the experimenter or physician to switch transgene expression 'on' and 'off' at will. In the last year, neuro-gene therapy has shown that brain defects in experimental disease models can be prevented and corrected, and that viral vectors and encoded transgenes can be made to diffuse over larger brain areas. In addition, the cause of vector-induced inflammation and immune responses have begun to be elucidated, so that rational approaches can be developed to avoid these complications. Further improvements in viral vectors will facilitate clinical trials in the near future.
Curr Opin Mol Ther 2002 Aug
PMID:Progress and challenges in viral vector-mediated gene transfer to the brain. 1222 74

Charcot-Marie-Tooth disease (CMT) is the most common inherited disorder of the peripheral nervous system, and mutations in neurofilaments have been linked to some forms of CMT. Neurofilaments are the major intermediate filaments of neurones, but the mechanisms by which the CMT mutations induce disease are not known. Here, we demonstrate that CMT mutant neurofilaments disrupt both neurofilament assembly and axonal transport of neurofilaments in cultured mammalian cells and neurones. We also show that CMT mutant neurofilaments perturb the localization of mitochondria in neurones. Accumulations of neurofilaments are a pathological feature of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, and diabetic neuropathy. Our results demonstrate that aberrant neurofilament assembly and transport can induce neurological disease, and further implicate defective neurofilament metabolism in the pathogenesis of human neurodegenerative diseases.
Hum Mol Genet 2002 Nov 01
PMID:Charcot-Marie-Tooth disease neurofilament mutations disrupt neurofilament assembly and axonal transport. 1239 95

Parkinson's disease (PD) is a progressive neurological disease caused by selective degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc). Although PD has been heavily researched, the precise etiology of nigral cell loss is still unknown and, consequently, treatment is largely symptomatic rather than preventive. There are conflicting data regarding the mode of dopaminergic cell death in PD and, hence, this remains controversial. Several mutations in specific genes have recently been linked with hereditary forms of PD. Although none of these mutations are seen in idiopathic disease cases, the elucidation of these genetic defects sheds light on the nature of idiopathic PD. It is possible that dopaminergic neurogenesis also contributes to the etiology of idiopathic PD. In addition, intracellular as well as extracellular substances found in the SNc are believed to function as damaging pathogenetic factors. These factors, and the interactions among them, might hold the secret to the underlying causes of the selective death of dopaminergic neurons in PD.
Trends Mol Med 2003 Mar
PMID:Molecular mechanisms of selective dopaminergic neuronal death in Parkinson's disease. 1265 34

We previously showed that ethanol regulates dopamine beta-hydroxylase (DBH) mRNA and protein levels in human neuroblastoma cells (Thibault, C., Lai, C., Wilke, N., Duong, B., Olive, M. F., Rahman, S., Dong, H., Hodge, C. W., Lockhart, D. J., and Miles, M. F. (2000) Mol. Pharmacol. 58, 1593-1600). DBH catalyzes norepinephrine synthesis, and several studies have suggested a role for norepinephrine in ethanol-mediated behaviors. Here, we performed a detailed analysis of mechanism(s) underlying ethanol regulation of DBH expression in SH-SY5Y cells. Transient transfection analysis showed that ethanol (25-200 mM) caused concentration- and time-dependent increases in DBH gene transcription. Progressive deletions identified ethanol-responsive sequences in the -262 to -142 bp region of the DBH gene promoter. Mutagenesis of cAMP-response element (CRE) sequences in this region abolished ethanol responsiveness while maintaining responsiveness to phorbol esters. Coexpression of dominant-negative CRE-binding protein greatly reduced ethanol induction of DBH. Inhibitors of protein kinase A, casein kinase II, and MAPK reduced ethanol induction of DBH promoter activity. Pharmacogenomic studies with microarrays showed that protein kinase A, MEK, and casein kinase II inhibitors blocked induction of DBH and a large subset of ethanol-responsive genes. These genes had diverse functional groupings, including multiple members of the MAPK and phosphatidylinositol signaling cascades. Real-time PCR analysis validated select microarray results. Taken together, these results suggest that ethanol regulation of DBH requires a functional CRE and its binding protein and may require interaction of multiple kinase pathways. This mechanism may also mediate ethanol responsiveness of a complex subset of genes in neural cells. These studies may have implications for behavioral responses to ethanol or mechanisms underlying ethanol-related neurological disease.
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PMID:Pharmacogenomic analysis of mechanisms mediating ethanol regulation of dopamine beta-hydroxylase. 1284 74

Recent advances in our understanding of RNA biology have focused attention on the potential of developing RNA-based strategies to treat human disease. Naturally occurring catalytic RNA molecules (ribozymes), their synthetic DNA counterparts (deoxyribozymes or DNAzymes), as well as the exciting, emerging technology of small interfering RNA which utilizes the highly conserved cellular RNA interference pathway, are being developed for therapeutic gene silencing purposes. The challenges for the application of this technology to neurological disease will be to identify appropriate disease targets, and to optimize the function, and particularly delivery of these RNA-based therapeutic molecules within the complex environment of the nervous system. This review will assess the potential of these RNA-based therapeutic strategies and the challenges ahead in their application to the treatment of neurological disease.
Curr Opin Mol Ther 2003 Aug
PMID:Ribozymes and siRNA for the treatment of diseases of the nervous system. 1451 81

Parkinson's disease (PD) is a debilitating neurodegenerative disorder arising from loss of dopaminergic neurons in the substantia nigra pars compacta and subsequent depletion of striatal dopamine levels, which results in distressing motor symptoms. The current standard pharmacological treatment for PD is direct replacement of dopamine by treatment with its precursor, levodopa (L-dopa). However, this does not significantly alter disease progression and might contribute to the ongoing pathology. Several features of PD make this disease one of the most promising targets for clinical gene therapy of any neurological disease. The confinement of the major pathology to a compact, localised neuronal population and the anatomy of the basal ganglia circuitry mean that global gene transfer is not required and there are well-defined sites for gene transfer. The multifactorial aetiology of idiopathic PD means that it is unlikely any single gene will cure the disease, and as a result at least three separate gene-transfer strategies are currently being pursued: transfer of genes for enzymes involved in dopamine production; transfer of genes for growth factors involved in dopaminergic cell survival and regeneration; and transfer of genes to reset neuronal circuitry by switching cellular phenotype. The merits of these strategies are discussed here, along with remaining hurdles that might impede transfer of gene therapy technology to the clinic as a treatment for PD.
Expert Rev Mol Med 2004 Mar 02
PMID:Gene therapy for Parkinson's disease. 1500 Jun 92

Neurological diseases are defined as an inappropriate function of the peripheral or central nervous system due to impaired electrical impulses throughout the brain and/or nervous system that may present with heterogeneous symptoms according to the parts of the system involved in these pathologic processes. Growing evidence on genetic components of neurological disease have been collected during recent years. Genetic studies have opened the way for understanding the underlying pathology of many neurological disorders. The outcome of current intense research into the genetics of neurological disorders will hopefully be the introduction of new diagnostic tools and the discovery of potential targets for new and more effective medications and preventive measures.
Expert Rev Mol Diagn 2004 May
PMID:Genetics of neurological disorders. 1513 99

Identification of biomarkers in neurological disease remains impeded by many obstacles. Among them are the availability of tissue at the site of pathology, poor clinical diagnostics, the complexity of the brain and a general dearth of functional end points and models for validation. However, advances in technology have helped to overcome these challenges. Some of these advances include standardization and increased efficiency in brain banking, novel techniques for brain imaging, improved methods for reducing tissue heterogeneity including laser capture microdissection, high-throughput genomics, new functional validation techniques such as RNA interference, and the development of new animal models of neurologic disease. In order to efficiently handle the wealth of information that will be gleaned from these new technologies, new integrated databasing protocols will be necessary. Access to these databases by researchers and clinicians is critical to the continued progress being made in biomarker identification in neurological disease. These challenges and ways to overcome them are presented here in the context of a disease known to be a robust model for biomarker identification, Alzheimer's disease.
Expert Rev Mol Diagn 2004 May
PMID:Biomarker identification in neurologic diseases: improving diagnostics and therapeutics. 1513 3

The catecholamine-oxidizing enzyme monoamine oxidase-B (MAO-B) has been hypothesized to be an important determining factor in the etiology of both normal aging and age-related neurological disorders such as Parkinson's disease (PD). Catalysis of substrate by the enzyme produces H2O2 which is a primary originator of oxidative stress which in turn can lead to cellular damage. MAO-B increases with age as does predisposition towards PD which has also been linked to increased oxidative stress. Inhibition of MAO-B, along with supplementation of lost dopamine via L-DOPA, is one of the major antiparkinsonian therapies currently in use. In this review, we address several factors contributing to a possible role for MAO-B in normal brain aging and neurological disease and also discuss the use of MAO-B inhibitors as drug therapy for these conditions.
Mol Neurobiol 2004 Aug
PMID:Perspectives on MAO-B in aging and neurological disease: where do we go from here? 1524 89


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