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Biomedical subjects

David K Simon

Publications and source records attributed to David K Simon.

13 recordsLinked to original sources
PubMed2006

Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators.

PPARgamma coactivator 1alpha (PGC-1alpha) is a potent stimulator of mitochondrial biogenesis and respiration. Since the mitochondrial electron transport chain is the main producer of reactive oxygen species (ROS) in most cells, we examined the effect of PGC-1alpha on the metabolism of ROS. PGC-1alpha is coinduced with several key ROS-detoxifying enzymes upon treatment of cells with an oxidative stressor; studies with RNAi or null cells indicate that PGC-1alpha is required for the induction of many ROS-detoxifying enzymes, including GPx1 and SOD2. PGC-1alpha null mice are much more sensitive to the neurodegenerative effects of MPTP and kainic acid, oxidative stressors affecting the substantia nigra and hippocampus, respectively. Increasing PGC-1alpha levels dramatically protects neural cells in culture from oxidative-stressor-mediated death. These studies reveal that PGC-1alpha is a broad and powerful regulator of ROS metabolism, providing a potential target for the therapeutic manipulation of these important endogenous toxins.

Animals↗
PubMed2006

Dystonia.

Explore the source record for details and available documents.

Botulinum Toxins↗
PubMed2005

Mitochondrial cyclic AMP response element-binding protein (CREB) mediates mitochondrial gene expression and neuronal survival.

Cyclic AMP response element-binding protein (CREB) is a widely expressed transcription factor whose role in neuronal protection is now well established. Here we report that CREB is present in the mitochondrial matrix of neurons and that it binds directly to cyclic AMP response elements (CREs) found within the mitochondrial genome. Disruption of CREB activity in the mitochondria decreases the expression of a subset of mitochondrial genes, including the ND5 subunit of complex I, down-regulates complex I-dependent mitochondrial respiration, and increases susceptibility to 3-nitropropionic acid, a mitochondrial toxin that induces a clinical and pathological phenotype similar to Huntington disease. These results demonstrate that regulation of mitochondrial gene expression by mitochondrial CREB, in part, underlies the protective effects of CREB and raise the possibility that decreased mitochondrial CREB activity contributes to the mitochondrial dysfunction and neuronal loss associated with neurodegenerative disorders.

Animals↗
PubMed2004

Somatic mitochondrial DNA mutations in single neurons and glia.

Somatic mitochondrial DNA (mtDNA) point mutations reach high levels in the brain. However, the cell types that accumulate mutations and the patterns of mutations within individual cells are not known. We have quantified somatic mtDNA mutations in 28 single neurons and in 18 single glia from post-mortem human substantia nigra of six control subjects. Both neurons and glia contain mtDNA with somatic mutations. Single neurons harbor a geometric mean (95% CI) of 200.3 (152.9-262.4) somatic mtDNA point mutations per million base pairs, compared to 133.8 (97.5-184.9) for single glia (p=0.0251). If mutations detected multiple times in the same cell are counted only once, the mean mutation level per million base pairs remains elevated in single neurons (146.9; 124.0-174.2) compared to single glia (100.5; 81.5-126.5; p=0.009). Multiple distinct somatic point mutations are present in different cells from the same subject. Most of these mutations are individually present at low levels (less than 10-20% of mtDNA molecules), but with high aggregate mutation levels, particularly in neurons. These mutations may contribute to changes in brain function during normal aging and neurodegenerative disorders.

Adult↗
PubMed2004

Mistaken diagnosis of psychogenic gait disorder in a man with status cataplecticus ("limp man syndrome").

We report on a 45-year-old man with a history of multiple psychiatric admissions for a gait disorder and episodic weakness thought to be psychogenic who was subsequently diagnosed with status cataplecticus due to narcolepsy. The gait difficulties resolved with venlafaxine. This case demonstrates that status cataplecticus can be misdiagnosed as a psychogenic gait disorder.

Carrier Proteins↗
PubMed2004

Evaluation of the role of Nurr1 in a large sample of familial Parkinson's disease.

Parkinson's disease (PD) is a common neurodegenerative disorder in humans with wide variability in the age of disease onset. Although the disease has been thought previously to occur sporadically in most patients, there is increasing evidence of a genetic contribution to the disorder. Recently, a polymorphic variant within intron 6 of the Nurr1 gene was reported to be associated with sporadic and familial PD. In an effort to identify susceptibility genes for PD, we have collected 783 PD patients from 372 families and 397 healthy controls from 217 families. PD patients and healthy controls were genotyped for the intron 6 insertion polymorphism by BseRI restriction endonuclease digestion. No significant difference in either homozygosity or heterozygosity for the 7048G7049 (IVS6 1361 +16insG) polymorphism was detected in the PD patient cohort as compared with the panel of healthy controls. Moreover, direct sequencing of exon 1 of the Nurr1 gene in PD patients failed to detect either of the two recently reported Nurr1 mutations identified in a small subset of a PD patient cohort. Taken together, these data suggest that genetic alteration at the Nurr1 locus is not a significant risk factor for the development of Parkinson's disease in our large sample of familial PD patients.

Adolescent↗
PubMed2004

Attenuation of free radical production and paracrystalline inclusions by creatine supplementation in a patient with a novel cytochrome b mutation.

Mitochondrial cytopathies are associated with increased free radical generation and paracrystalline inclusions. Paracrystalline inclusions were serendipitously found in a young male athlete with a very high respiratory exchange ratio during steady-state exercise; he also had an unusually low aerobic capacity. Direct sequencing of the mitochondrial DNA (mtDNA) coding regions revealed a novel missense mutation (G15497A) resulting in a glycine-->serine conversion at a highly conserved site in the cytochrome b gene in the subject, his mother, and sister. Cybrids, prepared by fusion of the subject's platelets with either U87MG rho degrees or SH-SY5Y rho degrees cells, generated higher basal levels of reactive oxygen species (ROS), had a lower adenosine triphosphate (ATP) content, and were more sensitive to oxygen and glucose deprivation and peroxynitrite generation compared to control cybrids with wild-type mtDNA. Cell survival was significantly enhanced with 50 mmol/L creatine monohydrate (CM) administration. The subject was also treated with CM (10 g/d) for a period of 5 weeks and a repeat muscle biopsy showed no paracrystalline inclusions. The results suggest that the development of exercise-induced paracrystalline inclusions may be influenced by the G15497A mtDNA mutation, and that CM mitigates against the pathological consequences of this mutation.

Adenosine Triphosphate↗
PubMed2004

Somatic mitochondrial DNA mutations in cortex and substantia nigra in aging and Parkinson's disease.

Oxidative damage to mitochondrial DNA (mtDNA) increases with age in the brain and can induce G:C to T:A and T:A to G:C point mutations. Though rare at any particular site, multiple somatic mtDNA mutations induced by oxidative damage or by other mechanisms may accumulate with age in the brain and thus could play a role in aging and neurodegenerative diseases. However, no prior study has quantified the total burden of mtDNA point mutation subtypes in the brain. Using a highly sensitive cloning and sequencing strategy, we find that the aggregate levels of G:C to T:A and T:A to G:C transversions and of all point mutations increase with age in the frontal cortex (FCtx). In the substantia nigra (SN), the aggregate levels of point mutations in young controls are similar to the levels in the SN or FCtx of elderly subjects. Extrapolation from our data suggests an average of 2.7 (FCtx) to 3.2 (SN) somatic point mutations per mitochondrial genome in elderly subjects. There were no significant differences between Parkinson's disease (PD) patients and age-matched controls in somatic mutation levels. These results indicate that individually rare mtDNA point mutations reach a high aggregate burden in FCtx and SN of elderly subjects.

Adolescent↗
PubMed2003

A heteroplasmic mitochondrial complex I gene mutation in adult-onset dystonia.

Mitochondrial DNA (mtDNA) mutations can cause rare forms of dystonia, but the role of mtDNA mutations in other types of dystonia is not well understood. We now report identification by sequencing, restriction endonuclease analyses, and clonal analyses of a heteroplasmic missense A to G base pair substitution at nucleotide position 3796 (A3796G) in the gene encoding the ND1 subunit of mitochondrial complex I in a patient with adult-onset dystonia, spasticity, and core-type myopathy. The mutation converts a highly conserved threonine to an alanine. The same mutation subsequently was identified in 2 of 74 additional unrelated adult-onset dystonia patients. A muscle biopsy was obtained from 1 of these 2 subjects and this revealed abnormalities of electron transport chain (ETC) activities. The mutation was absent in 64 subjects with early onset dystonia, 82 normal controls, and 65 subjects with Parkinson's disease or multiple system atrophy. The A3796G mutation previously has been reported in 3 of 226 subjects from mitochondrial haplogroup H. Each of the 3 subjects in our study harboring the A3796G mutation was also from haplogroup H. However, a subgroup analysis of haplogroup H subjects from our study indicates that the A3796G mutation is significantly overrepresented among haplogroup H adult-onset dystonia subjects compared with haplogroup H controls (P<0.01). This difference remains significant even after excluding the index patient (P=0.04). These data suggest that, among haplogroup H subjects, the presence of the A3796G mutation increases the risk of developing adult-onset dystonia.

Adolescent↗
PubMed2003

A common NURR1 polymorphism associated with Parkinson disease and diffuse Lewy body disease.

BACKGROUND: NURR1 plays a key role in mesencephalic dopaminergic neuron development and survival. A homozygous NURR1 polymorphism (a single base-pair insertion in intron 6) (NI6P) has been reported to be associated with Parkinson disease (PD). OBJECTIVE: To assess the association of the NI6P with PD and diffuse Lewy body disease. DESIGN: Case-control study. SETTING: Movement disorders clinic and tissue provided by brain banks. PATIENTS: Patients with pathologically proven PD (n = 37) or diffuse Lewy body disease (n = 35), neuropathologically normal control subjects (n = 59), those clinically diagnosed as having PD (n = 66), and spousal controls (n = 29). METHODS: Determining the frequency of heterozygotes and homozygotes for the NI6P by DNA sequencing and restriction endonuclease analyses. RESULTS: Overall, 41 (39.8%) of the 103 patients with PD were heterozygotes compared with 22 (25.0%) of the 88 controls (P =.03), with a relative risk (estimated from the odds ratio) for PD of 2.03 (95% confidence interval, 1.08-3.81) for heterozygotes vs wild type subjects. Heterozygotes were more frequent in the subgroup of patients with pathologically confirmed PD (18 [48.6%] of 37) vs controls (14 [23.7%] of 59) (P =.01), with a relative risk for PD of 2.84 (95% confidence interval, 1.17-6.88) for heterozygotes vs wild type subjects. In patients clinically diagnosed as having PD, heterozygotes were more frequent in early-onset cases (onset at < or =45 years) (10 [55.6%] of 18) compared with late-onset cases (onset at >45 years) (10 [23.8%] of 42) (P =.02) or spousal controls (8 [27.6%] of 29) (P =.06), with a relative risk for early-onset PD of 4.17 (95% confidence interval, 1.13-15.33) for heterozygotes vs subjects with 2 wild type alleles. The homozygous NI6P was not associated with PD, but was present in 6 (17.1%) of the 35 patients with diffuse Lewy body disease compared with 3 (5.1%) of the 59 controls (P =.06). CONCLUSIONS: The common heterozygous NI6P is associated with an increased risk of PD. An association of borderline significance was found for the homozygous NI6P and diffuse Lewy body disease.

Adult↗
PubMed2002

High aggregate burden of somatic mtDNA point mutations in aging and Alzheimer's disease brain.

The mitochondrial theory of aging proposes that mitochondrial DNA (mtDNA) accumulates mutations with age, and that these mutations contribute to physiological decline in aging and degenerative diseases. Although a great deal of indirect evidence supports this hypothesis, the aggregate burden of mtDNA mutations, particularly point mutations, has not been systematically quantified in aging or neurodegenerative disorders. Therefore, we directly assessed the aggregate burden of brain mtDNA point mutations in 17 subjects with Alzheimer's disease (AD), 10 elderly control subjects and 14 younger control subjects, using a PCR-cloning-sequencing strategy. We found that brain mtDNA from elderly subjects had a higher aggregate burden of mutations than brain mtDNA from younger subjects. The average aggregate mutational burden in elderly subjects was 2 x 10(-4) mutations/bp. The bulk of these mutations were individually rare point mutations, 60% of which changed an amino acid. Control experiments ensure that these results were not due to artifacts arising from PCR error, mistaken identification of nuclear pseudogenes or ex vivo oxidation. Cytochrome oxidase activity correlated negatively with increasing mutational burden. These findings significantly bolster the mitochondrial theory of aging.

Adult↗
PubMed2002

Spongiform encephalopathy mimicking corticobasal degeneration.

The presentation of subacute spongiform encephalopathies (SSE) is varied. The following case of SSE presented clinically similar to corticobasal degeneration. The SSE diagnosis was suspected because of magnetic resonance imaging (MRI) findings and confirmed pathologically.

Aged↗