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

RNA interference (RNAi) has emerged as a potential therapeutic approach for neurodegenerative diseases, particularly those associated with autosomal dominant patterns of inheritance. In proof of concept experiments, several groups have demonstrated efficacy of using viral vectors expressing short hairpin RNA (shRNA) directed against therapeutically relevant genes in mouse models of neurodegenerative diseases, including spinocerebellar ataxia, Amyotrophic Lateral Sclerosis, Huntington's Disease and amyloidosis (a pathological aspect of Alzheimer's Disease). Although viral-based RNAi has limitations that most likely will preclude its usage in humans, a few recent developments underscore the potential of non-viral-based delivery of relevant RNAi as therapeutics for neurodegenerative diseases. Here, I will review the recent literature on effectiveness of RNAi as a therapeutic strategy in mouse models of neurodegenerative diseases.
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PMID:RNAi silencing in mouse models of neurodegenerative diseases. 1745 35

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with progressive cell death of upper and lower motor neurons. In this study, we measured monocyte chemotactic protein-1 (MCP-1) and vascular endothelial growth factor (VEGF) levels in cerebrospinal fluid (CSF) and serum by enzyme-linked immunosorbent assay (ELISA) in 42 ALS patients, and compared these levels with those of control subjects with other neurodegenerative disorders or with those of normal controls. MCP-1 levels in CSF were significantly higher in ALS patients than in the control group. VEGF levels in CSF tended to be lower in ALS patients than in the control group, but not significantly. A positive correlation was found between MCP-1 levels in CSF of ALS patients and the total Norris scale. The elevation of MCP-1/VEGF ratio in CSF was more specific to ALS patients compared to other neurological diseases such as Parkinson's disease (PD) and spinocerebellar ataxia (SCA) and to controls. Our data suggested that both MCP-1 levels and MCP-1/VEGF ratio in CSF may be useful markers for the clinical diagnosis of ALS.
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PMID:Elevation of MCP-1 and MCP-1/VEGF ratio in cerebrospinal fluid of amyotrophic lateral sclerosis patients. 1767 28

Intrathecal baclofen (ITB) has evolved into a standard treatment for severe spasticity of both spinal and cerebral origin. The accumulated promising data from reported series of patients receiving ITB therapy together with the fact that spastic hypertonia commonly coexists with other neurological disorders have constituted a solid basis for offering this kind of treatment to patients suffering from other movement disorders. These include motor disorders such as dystonia, amyotrophic lateral sclerosis, status dystonicus, Hallervorden-Spatz disease, Freidreich's ataxia, "stiff-man" syndrome, but also vegetative states after revere brain trauma, anoxic encephalopathy or other pathology and more recently, various chronic pain syndromes. In this article, on the basis of the established applications of ITB therapy, we review the important emerging indications of this rewarding neuromodulation method and attempt to identify its future potential beneficial role in other chronic and otherwise refractory neurological disorders.
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PMID:Intrathecal baclofen in current neuromodulatory practice: established indications and emerging applications. 1769 70

A lesson from dominantly inherited forms of diverse neurodegenerative diseases, including amyotrophic lateral sclerosis, spinocerebellar ataxia and Huntington's disease, is that the selective dysfunction or death of the neuronal population most at risk in each disease is not mediated solely by damage from the mutant protein within the target neurons. The disease-causing toxic process, which in each case is caused by mutation in a gene that is widely or ubiquitously expressed, involves damage done by mutant proteins within the non-neuronal glial cells of the central nervous system, especially astrocytes and microglia. The disease mechanism is non-cell-autonomous, with toxicity derived from glia as a prominent contributor driving disease progression and in some instances even disease initiation.
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PMID:Glial cells as intrinsic components of non-cell-autonomous neurodegenerative disease. 1796 55

RNA interference using small inhibitory RNA (siRNA) has become a powerful tool to downregulate mRNA levels by cellular nucleases that become activated when a sequence homology between the siRNA and a respective mRNA molecule is detected. Therefore siRNA can be used to silence genes involved in the pathogenesis of various diseases associated with a known genetic background. As for many neurodegenerative disorders a causative therapy is unavailable, siRNA holds a promising option for the development of novel therapeutic strategies. Here we discuss different siRNA target strategies aiming for an allele-specific degradation of disease-inducing mRNA and we review the literature in the field of siRNA and its application in animal models of neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) and spinocerebellar ataxia (SCA1).
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PMID:The therapeutic potential of siRNA in gene therapy of neurodegenerative disorders. 1798 77

Mitochondria are key cytoplasmic organelles, responsible for generating cellular energy, regulating intracellular calcium levels, altering the reduction-oxidation potential of cells, and regulating cell death. Increasing evidence suggests that mitochondria play a central role in aging and in neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and Freidriech ataxia. Further, several lines of evidence suggest that mitochondrial dysfunction is an early event in most late-onset neurodegenerative diseases. Biochemical and animal model studies of inherited neurodegenerative diseases have revealed that mutant proteins of these diseases are associated with mitochondria. Mutant proteins are reported to block the transport of nuclear-encoded mitochondrial proteins to mitochondria, interact with mitochondrial proteins and disrupt the electron transport chain, induce free radicals, cause mitochondrial dysfunction, and, ultimately, damage neurons. This article discusses critical issues of mitochondria causing dysfunction in aging and neurodegenerative diseases, and discusses the potential of developing mitochondrial medicine, particularly mitochondrially targeted antioxidants, to treat aging and neurodegenerative diseases.
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PMID:Mitochondrial medicine for aging and neurodegenerative diseases. 1856 20

Canine degenerative myelopathy (DM) is a fatal neurodegenerative disease prevalent in several dog breeds. Typically, the initial progressive upper motor neuron spastic and general proprioceptive ataxia in the pelvic limbs occurs at 8 years of age or older. If euthanasia is delayed, the clinical signs will ascend, causing flaccid tetraparesis and other lower motor neuron signs. DNA samples from 38 DM-affected Pembroke Welsh corgi cases and 17 related clinically normal controls were used for genome-wide association mapping, which produced the strongest associations with markers on CFA31 in a region containing the canine SOD1 gene. SOD1 was considered a regional candidate gene because mutations in human SOD1 can cause amyotrophic lateral sclerosis (ALS), an adult-onset fatal paralytic neurodegenerative disease with both upper and lower motor neuron involvement. The resequencing of SOD1 in normal and affected dogs revealed a G to A transition, resulting in an E40K missense mutation. Homozygosity for the A allele was associated with DM in 5 dog breeds: Pembroke Welsh corgi, Boxer, Rhodesian ridgeback, German Shepherd dog, and Chesapeake Bay retriever. Microscopic examination of spinal cords from affected dogs revealed myelin and axon loss affecting the lateral white matter and neuronal cytoplasmic inclusions that bind anti-superoxide dismutase 1 antibodies. These inclusions are similar to those seen in spinal cord sections from ALS patients with SOD1 mutations. Our findings identify canine DM to be the first recognized spontaneously occurring animal model for ALS.
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PMID:Genome-wide association analysis reveals a SOD1 mutation in canine degenerative myelopathy that resembles amyotrophic lateral sclerosis. 1918 95

Covalent modification by SUMO polypeptides, or sumoylation, is an important regulator of the functional properties of many proteins. Among these are several proteins implicated in human diseases including cancer, Huntington's, Alzheimer's, and Parkinson's diseases, as well as spinocerebellar ataxia 1 and amyotrophic lateral sclerosis. Recent reports reveal two new examples of human disease-associated proteins that are SUMO modified: amyloid precursor protein and lamin A. These findings point to a function for sumoylation in modulating amyloid-beta peptide levels, indicating a potential role in Alzheimer's disease, and for decreased lamin A sumoylation as a causative factor in familial dilated cardiomyopathy.
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PMID:Sumoylation and human disease pathogenesis. 1928 83

The motor neuron diseases (MNDs) are a group of related neurodegenerative diseases that cause the relative selective progressive death of motor neurons. Exploring the molecular mechanisms underlying MND phenotypes has been hampered by their multifactorial nature and high incidence of sporadic cases, although genetic factors are considered to play a considerable role at present. However, environmental factors, especial exposure to neurotoxic substances, could induce neurotoxicity with the same phenotypes of specific MNDs. Organophosphate-induced delayed neuropathy (OPIDN) is a neurodegenerative disorder characterized by ataxia and progression to paralysis, with a concomitant distal axonal degeneration and secondary demyelination of central and peripheral axons. The inhibition and subsequent aging of neuropathy target esterase (NTE) by organophosphate has been proposed to be the initiating event in OPIDN. NTE is characterized to be a lysophospholipase/phospholipase B mostly in the nervous system to regulate phospholipid homeostasis. Brain-specific deletion of mouse NTE contributes to the behavioral defects characterized by neuronal loss. Recently, mutations in human NTE have also been shown to cause a hereditary spastic paraplegia called NTE-related motor neuron disorder with the same characteristics of OPIDN, which supported the role of NTE abnormalities in OPIDN, and raised the possibility that NTE pathway disturbances contribute to other MNDs. Together with the identified association of paraoxonase polymorphisms with amyotrophic lateral sclerosis, there is a possibility that neurotoxic substances contribute to MND in genetically vulnerable people by gene-environment interactions.
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PMID:Motor neuron diseases and neurotoxic substances: a possible link? 1949 9

Superoxide dismutase-1 (SOD1) and ataxin-3 are two neurodegenerative disease proteins in association with familial amyotrophic lateral sclerosis and Machado-Joseph disease/spinocerebellar ataxia type 3. Both normal and mutant types of SOD1 and ataxin-3 are degraded by the proteasome. It was recently reported that these two proteins are associated with the endoplasmic reticulum (ER). Mammalian gp78 is an E3 ubiquitin ligase involved in ER-associated degradation (ERAD). Here, we show that gp78 interacts with both SOD1 and ataxin-3. Overexpression of gp78 promotes the ubiquitination and degradation of these two proteins, whereas knockdown of gp78 stabilizes them. Moreover, gp78 represses aggregate formation of mutant SOD1 and protect cells against mutant SOD1-induced cell death. Furthermore, gp78 is increased in cells transfected with these two mutant proteins as well as in ALS mice. Thus, our results suggest that gp78 functions in the regulation of SOD1 and ataxin-3 to target them for ERAD.
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PMID:Gp78, an ER associated E3, promotes SOD1 and ataxin-3 degradation. 1966 Nov 82


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