Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A severe recessive cerebellar ataxia, Ataxia-Oculomotor Apraxia 2 (AOA2) and a juvenile onset form of dominant amyotrophic lateral sclerosis (ALS4) result from mutations of the Senataxin (SETX) gene. To begin characterization this disease protein, we developed a specific antibody to the DNA/RNA helicase domain of SETX. In murine brain, SETX concentrates in several regions, including cerebellum, hippocampus and olfactory bulb with a general neuronal expression profile, colocalizing with NeuN. In cultured cells, we found that SETX was cytoplasmically diffuse, but in the nucleus, SETX was punctate, colocalizing with fibrillarin, a marker of the nucleolus. In differentiated non-cycling cells, nuclear SETX was not restricted to the nucleolus but was diffuse within the nucleoplasm, suggesting cell-cycle-dependent localization. SETX missense mutations cluster within the N-terminus and helicase domains. Flag tagging at the N-terminus caused protein mislocation to the nucleoplasm and failure to export to the cytoplasm, suggesting that the N-terminus may be essential for correct SETX localization. We report here the first characterization of SETX protein, which may provide future insights into a new mechanism leading to neuron death.
 ...
PMID:Senataxin, the yeast Sen1p orthologue: characterization of a unique protein in which recessive mutations cause ataxia and dominant mutations cause motor neuron disease. 1664 29

Mutations in the Senataxin gene (SETX) are associated with autosomal recessive ataxia-ocular apraxia 2 (AOA2) and autosomal dominant juvenile ALS (ALS4). Here, the authors describe novel homozygous missense mutations in SETX, M274I, and R1294C, found in two siblings with ataxia, peripheral neuropathy, and increased serum alpha-fetoprotein level and three other siblings with heterozygous missense mutations who were neurologically asymptomatic. The results demonstrate that the double missense mutations are responsible for AOA2 but not for ALS4.
 ...
PMID:Autosomal recessive ataxia with peripheral neuropathy and elevated AFP: novel mutations in SETX. 1671 25

In the past decade, the genetic causes underlying familial forms of many neurodegenerative disorders, such as Huntington's disease, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, Friedreich ataxia, hereditary spastic paraplegia, dominant optic atrophy, Charcot-Marie-Tooth type 2A, neuropathy ataxia and retinitis pigmentosa, and Leber's hereditary optic atrophy have been elucidated. However, the common pathogenic mechanisms of neuronal death are still largely unknown. Recently, mitochondrial dysfunction has emerged as a potential 'lowest common denominator' linking these disorders. In this review, we discuss the body of evidence supporting the role of mitochondria in the pathogenesis of hereditary neurodegenerative diseases. We summarize the principal features of genetic diseases caused by abnormalities of mitochondrial proteins encoded by the mitochondrial or the nuclear genomes. We then address genetic diseases where mutant proteins are localized in multiple cell compartments, including mitochondria and where mitochondrial defects are likely to be directly caused by the mutant proteins. Finally, we describe examples of neurodegenerative disorders where mitochondrial dysfunction may be 'secondary' and probably concomitant with degenerative events in other cell organelles, but may still play an important role in the neuronal decay. Understanding the contribution of mitochondrial dysfunction to neurodegeneration and its pathophysiological basis will significantly impact our ability to develop more effective therapies for neurodegenerative diseases.
 ...
PMID:The role of mitochondria in inherited neurodegenerative diseases. 1680 75

During the past decade, numerous molecular mediators of neurodegenerative diseases and neurological disorders have been identified and validated, yet few novel therapies have emerged and the unmet medical needs remain high. These molecular mediators belong to target classes such as ion channels, neurotransmitters and neurotransmitter receptors, cytokines, growth factors, enzymes and other proteins. In some cases, substantial pre-clinical validation exists, but the molecular target has not been readily druggable with small molecules, proteins or antibodies. RNA interference represents a therapeutic approach applicable to such non-druggable targets. Both non-viral and viral delivery strategies are being undertaken for in vivo silencing of molecular targets by RNA interference, which has resulted in robust efficacy in animal models of Alzheimer's disease, ALS, Huntington's disease, spinocerebellar ataxia, anxiety, depression, neuropathic pain, encephalitis and glioblastoma. These proof-of-concept data in animal models, together with the commencement of clinical trials using RNA interference for macular degeneration and respiratory syncytial virus infection, point to the potential of direct RNA interference for neurological disorders and neurodegenerative diseases.
 ...
PMID:Therapeutic potential of RNA interference for neurological disorders. 1681 77

Copper deficiency in humans is a rare cause of myeloneuropathy that usually presents with a spastic ataxic gait, hyperreflexia, and distal sensory loss similar to that seen in patients with subacute combined degeneration. We describe three copper-deficient patients, two of whom were referred with a presumptive diagnosis of amyotrophic lateral sclerosis, who had progressive asymmetric weakness or electrodiagnostic findings of proximal and distal denervation suggestive of lower motor neuron disease. Copper replacement resulted in stabilization or mild improvement in weakness. The clinical spectrum of human copper deficiency should include lower motor neuron disease in addition to a syndrome of spastic ataxia.
 ...
PMID:Motor neuron disease associated with copper deficiency. 1692 46

Oxidative stress is an abnormal phenomenon occurring inside our cells or tissues when production of oxygen radicals exceeds their antioxidant capacity. Excess of free radicals damage essential macromolecules of the cell, leading to abnormal gene expression, disturbance in receptor activity, proliferation or cell dye, immunity perturbation, mutagenesis, protein or lipofushin deposition. Numerous human diseases involve during the pathological process such a stress, localized or general (in the same way as inflammation). In many serious diseases such as cancer, ocular degeneration (age related macular degeneration or cataract), neurodegenerative diseases (ataxia, amyotrophic lateral sclerosis, Alzheimer's disease) stress is the factor original. In familial amyotrophic lateral sclerosis the genetic abnormality occurred an abnormal coding for an antioxidant enzyme, copper-zinc super oxide dismutase. In various other diseases oxidative stress occur secondary to the initial disease but plays an important in role immune or vascular complications. This is the case in infectious disease such as AIDS or septic shock, Parkinson's disease or renal failure. So antioxidant treatment seems logical to be tested in these pathologies. But they have to be applied early in the process, before irreversible mechanisms. They need also to be prescribed at low doses as baseline free radical production have to be preserved to maintain useful activity that cannot be suppressed.
 ...
PMID:[Oxidative stress in human diseases]. 1711 68

Neurodegenerative diseases are now generally considered as a group of disorders that seriously and progressively impair the functions of the nervous system through selective neuronal vulnerability of specific brain regions. Alzheimer's disease is the most common neurodegenerative disease, followed in incidence by Parkinson's disease; much less common are frontotemporal dementia, Huntington's disease, amyothrophic lateral sclerosis (Lou Gehrig's disease), progressive supranuclear palsy, spinocerebellar ataxia, Pick's disease and, lastly, prion disease. In this review, the authors intend to survey new drugs in different clinical phases but not in the preclinical or discovery stages nor already in the market, with new molecules aimed at interrupting or at attenuating different pathogenic pathways of neurodegeneration and/or at ameliorating symptoms. Drugs in different pharmacological phases are under study or are ready to be introduced into therapy for Alzheimer's disease, which display anti-beta-amyloid activity or nerve growth factor-like activity or anti-inflammatory properties. Other drugs possess mixed mechanisms of action, such as acetylcholinesterase inhibition and impairment of beta-amyloid formation through inhibition of beta-amyloid precursor protein synthesis and/or modulation of secretase activity. Other therapeutic approaches are based on immunotherapy, control of metal ions interactions with beta-amyloid and ensuing oxidative reactions as well as metabolic or hormonal regulation. The symptomatic therapy of motor behaviour in Parkinson's disease, based on l-DOPA, is registering adenosine A(2A) receptor antagonists, monoamine oxidase B inhibitors and ion channel modulators, as well as dopamine uptake inhibitors and glutamate AMPA receptor antagonists. There are also many other drugs involved, including astrocyte-modulating agents, 5-HT(1A) agonists and alpha(2)-adrenergic receptor antagonists, which are targeted at preventing or ameliorating Parkinson's disease-related or l-DOPA-induced dyskinesias. Huntington's disease therapy envisages a Phase III drug, LAX-101, which displays antiapoptotic properties by promoting membrane stabilisation and mitochondrial integrity. Other drugs with antioxidant and antiapoptotic steroid-like and neuroprotective activity are under investigation for the therapy of the less common neurodegenerative diseases.
 ...
PMID:An update on pharmacological approaches to neurodegenerative diseases. 1715 54

Neurodegenerative diseases are responsible for agonizing symptoms that take their toll on the fragile human life. Aberrant protein processing and accumulation are considered to be the culprits of many classical neurodegenerative diseases such as Alzheimer's disease, tauopathies, Parkinson's disease, amyotrophic lateral sclerosis, hereditary spastic paraplegia and various polyglutamine diseases. However, recently it has been shown that toxic RNA species or disruption of RNA processing and metabolism may be partly to blame as clearly illustrated in spinal muscular atrophy, spinocerebellar ataxia 8 and fragile X-associated tremor/ataxia syndrome. At the dawn of the twenty-first century, the fruit fly or Drosophila melanogaster has taken its place at the forefront of an uphill struggle to unveil the molecular and cellular pathophysiology of both protein- and RNA-induced neurodegeneration, as well as discovery of novel drug targets. We review here the various fly models of neurodegenerative conditions, and summarise the novel insights that the fly has contributed to the field of neuroprotection and neurodegeneration.
 ...
PMID:The fly as a model for neurodegenerative diseases: is it worth the jump? 1719 23

Vitamin E is essential for neurological function. This fact, together with a growing body of evidence indicating that neurodegenerative processes are associated with oxidative stress, lead to the convincing idea that several neurological disorders may be prevented and/or cured by the antioxidant properties of vitamin E. In this review, some aspects related to the role of vitamin E against Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and ataxia with vitamin E deficiency will be presented.
 ...
PMID:Vitamin E and neurodegenerative diseases. 1730 57

In this Review, familial and sporadic neurological disorders reported to have an etiological link with DNA repair defects are discussed, with special emphasis placed on the molecular link between the disease phenotype and the precise DNA repair defect. Of the 15 neurological disorders listed, some of which have symptoms of progeria, six--spinocerebellar ataxia with axonal neuropathy-1, Huntington's disease, Alzheimer's disease, Parkinson's disease, Down syndrome and amyotrophic lateral sclerosis--seem to result from increased oxidative stress, and the inability of the base excision repair pathway to handle the damage to DNA that this induces. Five of the conditions (xeroderma pigmentosum, Cockayne's syndrome, trichothiodystrophy, Down syndrome, and triple-A syndrome) display a defect in the nucleotide excision repair pathway, four (Huntington's disease, various spinocerebellar ataxias, Friedreich's ataxia and myotonic dystrophy types 1 and 2) exhibit an unusual expansion of repeat sequences in DNA, and four (ataxia-telangiectasia, ataxia-telangiectasia-like disorder, Nijmegen breakage syndrome and Alzheimer's disease) exhibit defects in genes involved in repairing double-strand breaks. The current overall picture indicates that oxidative stress is a major causative factor in genomic instability in the brain, and that the nature of the resulting neurological phenotype depends on the pathway through which the instability is normally repaired.
 ...
PMID:Mechanisms of disease: DNA repair defects and neurological disease. 1734 92


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>