Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Apoptosis is an important process in the development of the nervous system. Typically, approximately 50% of the neurons apoptose during neurogenesis before the nervous system matures. However, recent paradigms implicate premature apoptosis and/or aberrations in the fine control of neuronal apoptosis in the pathogenesis of a variety of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal muscular atrophy, stroke, brain trauma, spinal cord injury, and diabetic neuropathy. This review will focus on the current concepts salient to understanding the apoptosis death program, the mediators and control of cellular apoptosis, and the relationship between aberrant apoptosis and genesis of neurodegenerative disorders. The discussion will also highlight current advances in methodology, such as utilization of neuronal cell lines and mutant animal models, in investigations of neuronal apoptotic death. The knowledge of apoptosis mechanisms could underpin the basis for development of novel therapeutic strategies and treatment modalities that are directed at control of the neuronal apoptotic death program.
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PMID:Apoptosis: a key in neurodegenerative disorders. 1618 Oct 84

Abnormal accumulation of disease-causing protein is a commonly observed characteristic in chronic neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and polyglutamine (polyQ) diseases. A therapeutic approach that could selectively eliminate would be a promising remedy for neurodegenerative disorders. Spinal and bulbar muscular atrophy (SBMA), one of the polyQ diseases, is a late-onset motor neuron disease characterized by proximal muscle atrophy, weakness, contraction fasciculations, and bulbar involvement. The pathogenic gene product is polyQ-expanded androgen receptor (AR), which belongs to the heat shock protein (Hsp) 90 client protein family. 17-Allylamino-17-demethoxygeldanamycin (17-AAG), a novel Hsp90 inhibitor, is a new derivative of geldanamycin that shares its important biological activities but shows less toxicity. 17-AAG is now in phase II clinical trials as a potential anti-cancer agent because of its ability to selectively degrade several oncoproteins. We have recently demonstrated the efficacy and safety of 17-AAG in a mouse model of SBMA. The administration of 17-AAG significantly ameliorated polyQ-mediated motor neuron degeneration by reducing the total amount of mutant AR. 17-AAG accomplished the preferential reduction of mutant AR mainly through Hsp90 chaperone complex formation and subsequent proteasome-dependent degradation. 17-AAG induced Hsp70 and Hsp40 in vivo as previously reported; however, its ability to induce HSPs was limited, suggesting that the HSP induction might support the degradation of mutant protein. The ability of 17-AAG to preferentially degrade mutant protein would be directly applicable to SBMA and other neurodegenerative diseases in which the disease-causing proteins also belong to the Hsp90 client protein family. Our proposed therapeutic approach, modulation of Hsp90 function by 17-AAG treatment, has emerged as a candidate for molecular-targeted therapies for neurodegenerative diseases. This review will consider our research findings and discuss the possibility of a clinical application of 17-AAG to SBMA and other neurodegenerative diseases.
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PMID:Modulation of Hsp90 function in neurodegenerative disorders: a molecular-targeted therapy against disease-causing protein. 1674 51

Degenerative processes within the nervous system are common features in disease entities such as dementia of Alzheimer type (DAT), Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS). ALS is a neurodegenerative disease with unknown etiology; widespread muscle wasting and respiratory failure lead to death within a few years. Denervation can be detected with electromyography and axonal deterioration monitored by motor unit number estimates. Several suggestions about the cause of ALS have emerged but no solid theory has yet precipitated. Lead or mercury exposure has been suggested. Exposure data alone cannot support this connection. Alterations in metal kinetics may underlie the deterioration of motor function observed in patients with ALS. In this review the role of metals in motor neuron disease is discussed. Both classic studies on exposure and recent understanding of metal binding proteins are considered. Aspects of peak exposure and excretion are merged toward an understanding of metal dynamics in ALS. An overview of chemical and electrophysiological investigations is given in the context of neurodegeneration.
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PMID:Metals in motor neuron diseases. 1701 70

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.
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PMID:The fly as a model for neurodegenerative diseases: is it worth the jump? 1719 23

Neurodegenerative disorders involve death of cell bodies, axons, dendrites and synapses, but it is surprisingly difficult to determine the spatiotemporal sequence of events and the causal relationships among these events. Neuronal compartments often crucially depend upon one another for survival, and molecular defects in one compartment can trigger cellular degeneration in distant parts of the neuron. Here, we consider the novel approaches used to understand these biologically complex and technically challenging questions in amyotrophic lateral sclerosis, spinal muscular atrophy, glaucoma, Alzheimer's disease, Parkinson's disease and polyglutamine disorders. We conclude that there is partial understanding of what degenerates first and why, but that controversy remains the rule not the exception. Finally, we highlight strategies for resolving these fundamental issues.
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PMID:Neuronal death: where does the end begin? 1733 56

RNA is not a simple intermediate between DNA and proteins. RNA is widely transcribed from a variety of genomic regions, and researchers are extensively exploring the functional roles and the regulations of non-coding RNAs and small RNAs including siRNAs and mRNAs. In addition, the human genome project disclosed that we humans carry as few as approximately 22,000 genes. Humans employ tissue-specific and developmental stage-specific alternative splicing to generate a large variety of proteins in a specific cell at a specific developmental stage. Neurological disorders are not the exceptions that can escape from aberrations of the splicing machinery. A large variety of neurological disorders is causally associated with RNA pathologies, but this lecture was mostly focused on aberrant splicings due to pathological alterations of splicing cis- and trans-elements. The neurological diseases covered include congenital myasthenic syndromes, genetic forms of Parkinson's disease, spastic paraplegia, myotonic dystrophy types 1 and 2, sporadic Alzheimer's disease, facioscapulohumeral dystrophy, fragile X-associated tremor/ ataxia syndrome, Rett syndrome, Prader-Willi syndrome, spinocerebellar atrophy type 8, and Waardenburg-Shah syndrome. Potential therapeutic modalities targeting RNA are addressed on congenital myasthenic syndromes, Duchenne muscular dystrophy, spinal muscular atrophy, and familial dysautonomia.
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PMID:[RNA pathologies in neurological disorders]. 1821 Aug 2

Etiology of Parkinson's disease (PD), amyotrophy lateral sclerosis (ALS), and Alzheimer's disease (AD) remains uncertain. Environmental factors probably play a role, but genetic influences may predispose certain individuals to develop each of these major neurodegenerative disorders. We describe our longitudinal observations concerning a Canadian family traced to Northern Germany. Autosornal dominant inheritance has been established. Affected members present with L-dopa responsive parkinsonism and amyotrophy. In the German portion of the family some individuals displayed only dementia or focal dystonia. Linkage analysis studies performed with polymorphic markers associated with 13 candidate genes provided no significant evidence for linkage with any of the genes examined. Positron emission tomography with [(18)F]-6-fluoro-L-dopa (FD) and [su11C]-raclopride (raclopride) of one affected subject revealed reduced striatal FD uptake particularly in putamen, and an increased raclopride striatum/background ratio. Postmortem levels of dopamine and its metabolites were greatly reduced in caudate and putamen of two patients. There was substantial neuronal loss in the substantia nigra and the presence of abundant eosinophilic granules (different than Lewy bodies) in surviving neurons. One of them also showed mild loss of anterior horn cells, while another showed abundant senile plaques and some neurofibrillary tangles in distribution and intensity typical of mild to moderate AD. Our report further describes this unique family with a combination of clinical features of PD, ALS, and AD. By studying kindreds like this we may learn more about the pathophysiology of sporadic forms of PD, ALS, or even AD.
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PMID:German-Canadian family (family A) with parkinsonism, amyotrophy, and dementia - Longitudinal observations. 1859 Oct 67

Gene therapy approaches to treat inherited and acquired disorders offer many unique advantages over conventional therapeutic approaches. For neurodegenerative diseases, gene therapy is particularly attractive due to the restricted bioavailability of conventional therapeutic substances to the affected structures of the brain and progressive nature of these diseases. With the development of lentiviral vector systems, many issues have been addressed and new delivery routes to the nervous system have been identified. Lentiviral vectors can efficiently deliver genes to postmitotic neuronal cell types offering long-term expression, can be generated in high titers, and do not give immunological complications. Various animal studies have demonstrated the effectiveness of these vectors to deliver therapeutic genes into the nervous system, as well as to model human diseases. This chapter will describe the basic features of lentiviral vectors, the progress, and their applications as a therapeutic strategy to treat diseases such as amyotrophic lateral sclerosis, spinal muscular atrophy, Parkinson's disease, and Huntington's disease.
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PMID:Gene therapy for neurodegenerative diseases based on lentiviral vectors. 1966 Jun 57

Neurodegenerative disorders (NDs) such as Huntington's disease, Alzheimer's disease, Parkinson disease, amyotrophic lateral sclerosis, spinal muscular atrophy, Friedreich's ataxia, and others are multi-factorial illnesses, in which many pathways (still poorly understood) act serially and in parallel to give a determined pathologic phenotype. Thus, presently there are no effective cures for these diseases. Some phenotypic as well as mechanistic features, common to the most of NDs, can be linked to epigenetic defects, that can lead to alteration of acetylation homeostasis and impairment of the histone acetyltransferase (HAT): histone deacetylase (HDAC) balance. Here we survey most of the recent applications of HDAC inhibitors in the cited NDs, and we make the point of our (up to now) knowledge about the involvement of singular HDAC/SIRT isoform in NDs and other CNS pathologies.
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PMID:Histone deacetylase inhibitors and neurodegenerative disorders: holding the promise. 1975 Dec 7

Parkinson's disease (PD) is a common neurodegenerative disorder. The motor neuron degeneration 2 mutant (mnd2) mouse exhibits loss of striatal neurons, muscle wasting, weight loss, and death within 40days of birth, and is considered to be a useful animal model of PD. mnd2 was identified as an autosomal recessive mutation in the HtrA2/Omi gene, which encodes a mitochondrial serine protease. Omi-deficient mitochondria are more sensitive to mitochondrial permeability transition (mPT), which raises the possibility that mPT plays a role in motor neurodegeneration in mnd2 mice. Given that cyclophilin D (CypD)-deficient mitochondria are resistant to mPT, we examined whether CypD-dependent mPT is involved in the pathogenesis of neurodegenerative disorders in mnd2 mice by generating CypD-deficient mnd2 mice. Brain mitochondria isolated from CypD-deficient mnd2 mice were more resistant to Ca(2+)-induced mPT than those of mnd2 mice. However, both mnd2 mice and CypD-deficient mnd2 mice showed similar survival periods and phenotypes, including the lack of weight gain, muscle wasting, and resting tremor. Our data suggest that CypD-dependent mPT does not play a major role in neurodegeneration in mnd2 mice.
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PMID:Cyclophilin D-dependent mitochondrial permeability transition is not involved in neurodegeneration in mnd2 mutant mice. 2012 86


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