Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A free radical is a highly reactive chemical species that can react with organic macromolecules leading to cell and tissue damage and consequent functional disruption. Free radical or oxidative injury is increasingly recognized as an important factor in the pathophysiology of many human diseases, including those that affect the nervous system. This review summarizes important evidence implicating oxidative injury in the pathogenesis and progression of many important neurological disorders, including cerebrovascular disease, epilepsy, amyotrophic lateral sclerosis, and Huntington's disease. Results of controlled clinical trials of various antioxidant therapies in neurological disease performed to date are also highlighted.
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PMID:Oxidative injury in the nervous system. 978 9

Review During the past 10 years (the "decade of the brain"), some of the genetic causes of many of the primary neurodegenerative diseases, which include Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, prion disease, and many ataxic syndromes, have been found. These breakthroughs mean that for many of these diseases we now know the initiating trigger as well as the final outcome. These diseases have many pathological mechanisms in common, and there may be relatively few pathways to neuronal death seen in these disorders. Thus, treatment strategies developed for a particular disease may be found to have efficacy in more than one disorder.
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PMID:Genetic classification of primary neurodegenerative disease. 980 38

Review The neurodegenerative disorders, a heterogeneous group of chronic progressive diseases, are among the most puzzling and devastating illnesses in medicine. Some of these disorders, such as Alzheimer's disease, amyotrophic lateral sclerosis, the prion diseases, and Parkinson's disease, can occur sporadically and, in some instances, are caused by inheritance of gene mutations. Huntington's disease is acquired in an entirely genetic manner. Transgenic mice that express disease-causing genes recapitulate many features of these diseases. This review provides an overview of transgenic mouse models of familial amyotrophic lateral sclerosis, familial Alzheimer's disease, and Huntington's disease and the emerging insights relevant to the underlying molecular mechanisms of these diseases.
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PMID:Genetic neurodegenerative diseases: the human illness and transgenic models. 980 39

Molecular genetic analyses have elucidated a class of inherited neurodegenerative disorders caused by expanded CAG repeats encoding polyglutamines (e.g. Huntington disease and Machado-Joseph disease). Proteins containing expanded polyglutamine repeats appear to precipitate by self-aggregation and, as a result, produce a core disease-related phenotype: neuronal cell death or degeneration. In other neurodegenerative disorders, such as Alzheimer disease, prion disease, Parkinson disease and amyotrophic lateral sclerosis, precipitation of abnormal proteins is also now considered to play a key role. These observations might lead to the elucidation of universal mechanisms for neurodegeneration and to effective treatments for many neurodegenerative disorders.
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PMID:Protein precipitation: a common etiology in neurodegenerative disorders? 982 28

MSA is a complex disorder, with regard to its pathology and cause as well as its clinical diagnosis and treatment. Although a number of clinical treatments may improve quality of life for these patients, given the widespread pathology present, symptomatic treatment, particularly that involving neurotransmitter replacement, is likely to remain difficult. Truly effective treatment for these patients is likely to depend on an understanding of the underlying pathogenic mechanisms and methods to halt or reverse disease progression. A firm understanding of the classification of these disorders is the first step to understanding the relevant pathogenic mechanisms. The finding of intracytoplasmic glial inclusion bodies provides a compelling piece of evidence that SND, OPCA, and SDS do, in fact, belong to one nosologic entity. These inclusions do not seem to be present in familial cases of OPCA; thus, they may provide a means to improve diagnostic specificity as well as sensitivity. With the ability to define clearly the entity of MSA, an understanding of the pathophysiology can be developed along with other degenerative neurologic diseases, including Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and Huntington's disease.
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PMID:Multiple system atrophy. 1009 84

The Golgi apparatus (GA) of the large pyramidal motor neurons in the cerebral cortex (Betz cells), was examined in sixteen patients with sporadic amyotrophic lateral sclerosis (ALS), in one patient with familial ALS (FALS), and in ten non-ALS age matched controls including one patient with Huntington's disease and one patient with a brain infarct. The GA was immunostained with an antibody against the MG-160 protein, a conserved sialoglycoprotein of the medial cisternae of the organelle. In ALS, 13.2% of counted Betz cells had fragmented GA in contrast to 0.6% in the ten non-ALS controls. The fragmentation of the GA of Betz cells was identical to that previously reported in spinal cord motor neurons from patients with sporadic ALS and in transgenic mice expressing the G93A mutation of the gene encoding the Cu/Zn superoxide dismutase. The striking morphological similarity between the fragmentation of the GA observed in Betz cells and in spinal cord motor neurons suggests that a similar pathogenic mechanism is responsible for both, and that the fragmentation of the GA of the spinal cord motor neurons is not a consequence of deafferentation due to the degeneration of the Betz cells.
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PMID:Fragmentation of the Golgi apparatus of Betz cells in patients with amyotrophic lateral sclerosis. 1022 16

Psychosis has been recognized as a common feature in neurodegenerative disease for many years. Hallucinations, delusions, and other psychotic phenomena occur in a wide range of degenerative disorders including Alzheimer disease, Huntington disease, Parkinson's disease, diffuse Lewy body disease, "Parkinson plus" syndromes, Pikc's disease, and other frontotemporal degenerations, amyotrophic lateral sclerosis, and prion associated diseases. It is also interesting that neurodegenerative disease-type dementia may be a feature in some psychotic illnesses such as schizophrenia. Clinical evaluation of psychosis in the setting of dementia presents a significant challenge for clinicians and researchers. Amnesia, language or speech impairments, and behavioral problems amy distort and obscure the presentation of symptoms. However, recognition and understanding of the psychotic manifestations may lead to the institution of more effective therapeutic or preventive options that can serve to delay long term care placement and improve patient and caregiver quality of life. In addition, a more comprehensive understanding of the pathophysiology, neuroanatomical substrates, and distinctive pathological features underlying the development of psychotic symptoms in neurodegenerative diseases may provide important insights into psychotic processes in general.
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PMID:Psychosis in Neurodegenerative Disease. 1032 Apr 31

Glutamic acid is the principal excitatory neurotransmitter in the mammalian central nervous system. Glutamic acid binds to a variety of excitatory amino acid receptors, which are ligand-gated ion channels. It is activation of these receptors that leads to depolarisation and neuronal excitation. In normal synaptic functioning, activation of excitatory amino acid receptors is transitory. However, if, for any reason, receptor activation becomes excessive or prolonged, the target neurones become damaged and eventually die. This process of neuronal death is called excitotoxicity and appears to involve sustained elevations of intracellular calcium levels. Impairment of neuronal energy metabolism may sensitise neurones to excitotoxic cell death. The principle of excitotoxicity has been well-established experimentally, both in in vitro systems and in vivo, following administration of excitatory amino acids into the nervous system. A role for excitotoxicity in the aetiology or progression of several human neurodegenerative diseases has been proposed, which has stimulated much research recently. This has led to the hope that compounds that interfere with glutamatergic neurotransmission may be of clinical benefit in treating such diseases. However, except in the case of a few very rare conditions, direct evidence for a pathogenic role for excitotoxicity in neurological disease is missing. Much attention has been directed at obtaining evidence for a role for excitotoxicity in the neurological sequelae of stroke, and there now seems to be little doubt that such a process is indeed a determining factor in the extent of the lesions observed. Several clinical trials have evaluated the potential of antiglutamate drugs to improve outcome following acute ischaemic stroke, but to date, the results of these have been disappointing. In amyotrophic lateral sclerosis, neurolathyrism, and human immunodeficiency virus dementia complex, several lines of circumstantial evidence suggest that excitotoxicity may contribute to the pathogenic process. An antiglutamate drug, riluzole, recently has been shown to provide some therapeutic benefit in the treatment of amyotrophic lateral sclerosis. Parkinson's disease and Huntington's disease are examples of neurodegenerative diseases where mitochondrial dysfunction may sensitise specific populations of neurones to excitotoxicity from synaptic glutamic acid. The first clinical trials aimed at providing neuroprotection with antiglutamate drugs are currently in progress for these two diseases.
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PMID:The role of excitotoxicity in neurodegenerative disease: implications for therapy. 1033 61

At present, 8 inherited neurodegenerative disorders (e.g. Huntington disease, Machado-Joseph disease, etc.) are identified to be caused by the polyglutamine-coding CAG triplet expansions in the responsible genes. These disorders commonly demonstrate dominant inheritance, if autosomal, and late onset of their manifestations. Interestingly, the longer expansions result in earlier onset and more severe clinical manifestations. Proteins containing expanded polyglutamine repeats appear to precipitate by self-aggregation, and as a result produce a core disease-related phenotype: neuronal cell death or degeneration. Given that polyglutamine aggregation might be central in neurodegeneration, the parameters that determine the feasibility of the polyglutamines to aggregate would determine the age of onset and the clinical severity. These parameters are postulated to be the concentration and the length of polyglutamines, which is supported by clinical and experimental observations. The stronger neuronal degenerations are always accompanied by the longer polyglutamine stretches and by the higher concentration of the expanded polyglutamines. In other neurodegenerative disorders, such as Alzheimer disease, prion disease, Parkinson disease and amyotrophic lateral sclerosis, precipitation of abnormal proteins is also now considered to play a key role. These observations might lead to the elucidation of universal mechanisms for neurodegeneration and to treatments effective for many neurodegenerative disorders.
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PMID:[Recent progress in the research field on triplet repeat diseases]. 1034 35

Coenzyme Q10 (CoQ10) is an essential cofactor of the electron transport chain as well as an important antioxidant. Previous studies have suggested that it may exert therapeutic effects in patients with known mitochondrial disorders. We investigated whether it can exert neuroprotective effects in a variety of animal models. We have demonstrated that CoQ10 can protect against striatal lesions produced by both malonate and 3-nitropropionic acid. It also protects against MPTP toxicity in mice. It extended survival in a transgenic mouse model of amyotrophic lateral sclerosis. We demonstrated that oral administration can increase plasma levels in patients with Parkinson's disease. Oral administration of CoQ10 significantly decreased elevated lactate levels in patients with Huntington's disease. These studies therefore raise the prospect that administration of CoQ10 may be useful for the treatment of neurodegenerative diseases.
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PMID:Coenzyme Q10 administration and its potential for treatment of neurodegenerative diseases. 1041 39


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