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)

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.
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PMID:Mechanisms of disease: DNA repair defects and neurological disease. 1734 92

The accumulation of DNA damage has been widely implicated in premature aging and neurodegeneration. Progeroid syndromes with defects in the cellular response to DNA damage suggest that progressive genome instability represents an important aspect of the aging process. Moreover, most of the major neurodegenerative diseases are characterized by the accumulation of neuronal DNA damage, suggesting that impaired DNA repair mechanisms might be relevant to both premature aging and neurodegeneration. Two progeroid syndromes, Hutchinson-Gilford progeria syndrome and Werner's syndrome, are characterized by clinical features mimicking physiological aging at an early age and molecular studies have implicated decreased cell proliferation and altered DNA-damage responses as common causal mechanisms in the pathogenesis of both diseases. Defects in nucleotide excision repair cause three distinct human diseases: xeroderma pigmentosum, Cockayne's syndrome and trichothiodystrophy; each of them is characterized by premature onset of pathologies that overlap with those associated with old age in humans. Increasing evidence also suggests that an impaired DNA repair, particularly the base excision repair pathway, might play a fundamental role in the development of age-related neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington' s disease. Here, we review the current knowledge on the role of DNA repair in premature aging and neurodegenerative diseases.
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PMID:DNA repair in premature aging disorders and neurodegeneration. 2029 65

Micronuclei (MNi) can originate either from chromosome breakage or chromosome malsegregation events and are therefore ideal biomarkers to investigate genomic instability. Studies in peripheral lymphocytes of patients with neurodegenerative diseases, mainly Alzheimer's disease (AD) and Parkinson's disease (PD), revealed an increased micronucleus (MN) frequency in both disorders but originating mainly from chromosome malsegregation events in AD and from chromosome breakage events in PD. Studies in other neurodegenerative diseases are largely missing, and some data in premature ageing disorders characterised by neurodegeneration and/or neurological complications, such as Ataxia telangiectasia, Werner's syndrome, Down's syndrome (DS) and Cockayne's syndrome, indicate that MNi increase with ageing in cultured cells. An increased frequency of aneuploidy characterises several tissues of AD patients, as well as of individuals at increased risk to develop AD, such as mothers of DS individuals and DS subjects themselves. The use of the buccal MN cytome assay in AD and DS subjects allowed finding significant changes in the MN frequency as well as other cellular modifications reflecting reduced regenerative capacity compared to age- and gender-matched controls. These changes in buccal cytome ratios may prove useful as potential future diagnostics to identify individuals of increased risk for these disorders.
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PMID:Association of micronucleus frequency with neurodegenerative diseases. 2116 87

Deficiency in repair of nuclear and mitochondrial DNA damage has been linked to several neurodegenerative disorders. Many recent experimental results indicate that the post-mitotic neurons are particularly prone to accumulation of unrepaired DNA lesions potentially leading to progressive neurodegeneration. Nucleotide excision repair is the cellular pathway responsible for removing helix-distorting DNA damage and deficiency in such repair is found in a number of diseases with neurodegenerative phenotypes, including Xeroderma Pigmentosum and Cockayne syndrome. The main pathway for repairing oxidative base lesions is base excision repair, and such repair is crucial for neurons given their high rates of oxygen metabolism. Mismatch repair corrects base mispairs generated during replication and evidence indicates that oxidative DNA damage can cause this pathway to expand trinucleotide repeats, thereby causing Huntington's disease. Single-strand breaks are common DNA lesions and are associated with the neurodegenerative diseases, ataxia-oculomotor apraxia-1 and spinocerebellar ataxia with axonal neuropathy-1. DNA double-strand breaks are toxic lesions and two main pathways exist for their repair: homologous recombination and non-homologous end-joining. Ataxia telangiectasia and related disorders with defects in these pathways illustrate that such defects can lead to early childhood neurodegeneration. Aging is a risk factor for neurodegeneration and accumulation of oxidative mitochondrial DNA damage may be linked with the age-associated neurodegenerative disorders Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Mutation in the WRN protein leads to the premature aging disease Werner syndrome, a disorder that features neurodegeneration. In this article we review the evidence linking deficiencies in the DNA repair pathways with neurodegeneration.
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PMID:DNA repair deficiency in neurodegeneration. 2155 Mar 79

Oxidative stress (OS) and mitochondrial dysfunction (MD) have been extensively studied and defined as therapeutic targets in Down syndrome (DS). Though originally associated to individual genes located in supernumerary chromosome 21, OS and MD metabolic compromises appear to be linked to whole genome functionally defined transcriptional fingerprints that further exacerbate the contribution of critical genes in DS-AD pathology. As the main ROS generator, mitochondrial complex double-membrane organization, tightly regulated fission/fusion dynamics, and involvement in critical pathways, makes it particularly vulnerable to functional alterations. Consequently, mitochondrial network morphology depends on its metabolic state and has been used as an indicator of cellular homeostasis. Initial qualitative categorization, suitable for sparse arranged fragments analysis, were proven to be ineffective to measure network connectivity and replaced by innovative tools that involve the transformation of raw images to linear skeletons. These manipulations allowed the development of a new generation of structural parameters, such as mean degree value (MDV). Alterations in DS mitochondrial networks include increased frequency of aberrant morphologies, shorter mitochondrial fragments, and significantly lower mitochondrial network connectivity. Similar structural and functional mitochondrial defects are common to other neurodegenerative diseases, such as Parkinson disease and Prion disease, and to a progeroid syndrome like HGPS. Therapeutic interventions aimed to either increase mitochondrial biogenesis or diminish OS using mitochondrial-targeted antioxidants, successfully restored mitochondrial activity and structural organization, confirming the strong correlation between network form and function.
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PMID:The Shape of Mitochondrial Dysfunction in Down Syndrome. 3083 Jul 26

Oxidative stress develops as a response to injury and reflects a breach in the cell's antioxidant capacity. Therefore, the fine-tuning of reactive oxygen species (ROS) generation is crucial for preserving cell's homeostasis. Mitochondria are a major source and an immediate target of ROS. Under different stimuli, including oxidative stress and impaired quality control, mitochondrial constituents (e.g., mitochondrial DNA, mtDNA) are displaced toward intra- or extracellular compartments. However, the mechanisms responsible for mtDNA unloading remain largely unclear. While shuttling freely within the cell, mtDNA can be delivered into the extracellular compartment via either extrusion of entire nucleoids or the generation and release of extracellular vesicles. Once discarded, mtDNA may act as a damage-associated molecular pattern (DAMP) and trigger an innate immune inflammatory response by binding to danger-signal receptors. Neuroinflammation is associated with a large array of neurological disorders for which mitochondrial DAMPs could represent a common thread supporting disease progression. The exploration of non-canonical pathways involved in mitochondrial quality control and neurodegeneration may unveil novel targets for the development of therapeutic agents. Here, we discuss these processes in the setting of two common neurodegenerative diseases (Alzheimer's and Parkinson's disease) and Down syndrome, the most frequent progeroid syndrome.
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PMID:Mitochondrial Dysfunction, Oxidative Stress, and Neuroinflammation: Intertwined Roads to Neurodegeneration. 3270 49