Limited-time exposure to mitochondrial toxins may lead to chronic progressive neurodegenerative diseases.
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Animals↗
Biomedical subjects
M F Beal
Publications and source records attributed to M F Beal.
Absence of p53: no effect in a transgenic mouse model of familial amyotrophic lateral sclerosis.
Familial amyotrophic lateral sclerosis (ALS) has been linked in some families to dominantly inherited mutations in the gene encoding copper-zinc superoxide dismutase 1 (Cu-Zn SOD1). Transgenic mice expressing a mutant human Cu-Zn SOD1 (G93A) develop a dominantly inherited adult-onset paralytic disorder that replicates many of the clinical and pathological features of familial ALS. Increased p53 immunoreactivity has been reported in the motor cortex and spinal ventral horns of postmortem tissue from ALS patients. The nuclear phosphoprotein p53 is an important regulator of cellular proliferation, and increasing evidence supports the role of p53 in regulating cellular apoptosis. To assess the role of p53-mediated apoptosis in amyotrophic lateral sclerosis, mice deficient in both p53 alleles (p53-/-) were crossed with transgenic mice expressing the G93A mutant (G93A+), creating novel transgenic knockout mice. The animals (p53 +/+G93A+, p53+/-G93A+, p53-/-G93A+) were examined at regular intervals for cage activity, upper and lower extremity strength, and mortality. At 120 days from birth mice from each genotype were sacrificed, and L2-L3 anterior horn motor neurons were counted. There was no significant difference in time to onset of behavioral decline, mortality, or motor neuron degeneration between the different genotypes. Despite evidence that p53 plays an important role after acute neuronal injury, the current study suggests that p53 is not significantly involved in cell death in the G93A+ transgenic mouse model of familial ALS.
Amyotrophic Lateral Sclerosis↗
Mitochondrial dysfunction and oxidative stress in aging and neurodegenerative disease.
A major risk factor for neurodegenerative diseases such as Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD) and progressive supranuclear palsy (PSP) is aging. Two processes that have been implicated in aging are free radical-induced oxidative damage and mitochondrial dysfunction. A progressive impairment of mitochondrial function and/or increased oxidative damage has been suggested to play critical roles in the pathogenesis of these neurodegenerative diseases. For example, decreased complex I activity, increased oxidative damage and altered activities of antioxidant defense enzymes have been demonstrated in PD. In AD, decrements in complex IV activity and increased oxidative damage have been reported. Reductions in complex II activity, increased cortical lactate levels and oxidative damage have been described in HD. Some familial ALS cases are associated with mutations in the gene for Cu,Zn superoxide dismutase (SOD1) while increased oxidative damage is observed in sporadic ALS. Studies in PSP have demonstrated regionally specific reductions in brain and muscle mitochondrial function, hypofrontality and increased oxidative damage. Altogether, the age-dependent onset and progressive course of these neurodegenerative diseases may ultimately highlight an association between aging, mitochondrial impairment and oxidative stress.
Aging↗
Neuroprotective and neurorestorative strategies for neuronal injury.
Mechanisms of neuronal cell death in apoptosis and necrosis are examined. Neurotoxic processes underlying cellular destruction may involve N-methyl-D-aspartate (NMDA) receptor activation and/or activation of neuronal nitric oxide synthase but the depletion of energy and generation of free radicals appears to be critical. In Alzheimer's disease the damaging effects of peroxynitrite and exposure to beta-amyloid peptide is evident. Mitochondrial dysfunction is involved in several neurodegenerative diseases including Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease as well as Alzheimer's disease and in these disorders the innovations offered by techniques ranging from transgenic mouse models of the disorder to cell culture preparations are remarkable. Agents of neuroprotection and neurorestoration possess either characteristics specific to particular disorders or have a general applicability or both. The vast array of agents available are for the most part the objectives of laboratory examinations but an increasing selection of compounds are reaching the clinical necessities thereby influencing current strategic notions to modify tactical contingencies. Among the agents listed are included: inhibitors of the enzyme poly-ADP-ribose polymerase, inhibition of apoptotic cell death, agents acting on mitochondrial permeability transition, excitatory amino acid antagonists, applications of neurotrophins, immunophilins, agents influencing heme oxygenase-1 expression and iron sequestration in aging astroglia, improvements in mitochondrial energy production or buffering, and finally dopaminemimetics with differential affinities for dopamine receptors.
Journal Article↗
Prospects for redox-based therapy in neurodegenerative diseases.
Accumulating evidence supports a primary role for perturbations in redox metabolism in the pathogenesis of many neurodegenerative diseases. This evidence derives mainly from molecular genetic analysis, direct observation from post-mortem human brain, and biochemical, pathologic, and therapeutic studies in transgenic and other animal models of neurodegeneration. We review here the evidence for redox-mediated pathogenesis in neurodegenerative diseases. The emerging class of redox-based therapeutic agents is then discussed. Drugs of this class are distinguished by their proximate effect, which is oxidative and not phosphorylative.
Journal Article↗
Energetics in the pathogenesis of neurodegenerative diseases.
Mitochondria have been linked to both necrotic and apoptotic cell death, which are thought to have a major role in the pathogenesis of neurodegenerative diseases. Recent evidence shows that nuclear gene defects affecting mitochondrial function have a role in the pathogenesis of Friedreich's ataxia, Wilson's disease and hereditary spastic paraplegia. There is also accumulating evidence that mitochondrial dysfunction might have a role in the pathogenesis of amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease and Alzheimer's disease. If this is so, a number of therapeutic targets are implicated that might result in novel treatments for neurodegenerative diseases.
Animals↗
Nonlinear decrease over time in N-acetyl aspartate levels in the absence of neuronal loss and increases in glutamine and glucose in transgenic Huntington's disease mice.
Mice transgenic for exon I of mutant huntingtin, with 141 CAG repeats, exhibit a profound symptomatology characterized by weight loss, motor disorders, and early death. We performed longitudinal analysis of metabolite levels in these mice using NMR spectroscopy in vivo and in vitro. These mice exhibited a large (53%), nonlinear drop in in vivo N-acetyl aspartate (NAA) levels over time, commencing at approximately 6 weeks of age, coincident with onset of symptoms. These drops in NAA levels occurred in the absence of neuronal death as measured by postmortem Nissl staining and neuronal counting but in the presence of nuclear inclusion bodies. In addition to decreased NAA, these mice showed a large elevation of glucose in the brain (600%) consistent with a diabetic profile and elevations in blood glucose levels both before and after glucose loading. In vitro NMR analysis revealed significant increases in glutamine (100%), taurine (95%) cholines (200%), and scyllo-inositol (333%) and decreases in glutamate (24%) and succinate (47%). These results lead to two conclusions. NAA is reflective of the health of neurons and thus is a noninvasive marker, with a temporal progression similar to nuclear inclusion bodies and symptoms, of neuronal dysfunction in transgenic mice. Second, the presence of elevated glutamine is evidence of a profound metabolic defect. We present arguments that the elevated glutamine results from a decrease in neuronal-glial glutamate-glutamine cycling and a decrease in glutaminase activity.
Animals↗
Malonate and 3-nitropropionic acid neurotoxicity are reduced in transgenic mice expressing a caspase-1 dominant-negative mutant.
Increasing evidence implicates caspase-1-mediated cell death as a major mechanism of neuronal death in neurodegenerative diseases. In the present study we investigated the role of caspase-1 in neurotoxic experimental animal models of Huntington's disease (HD) by examining whether transgenic mice expressing a caspase-1 dominant-negative mutant are resistant to malonate and 3-nitropropionic acid (3-NP) neurotoxicity. Intrastriatal injection of malonate resulted in significantly smaller striatal lesions in mutant caspase-1 mice than those observed in littermate control mice. Caspase-1 was significantly activated following malonate intrastriatal administration in control mice but significantly attenuated in mutant caspase-1 mice. Systemic 3-NP treatment induced selective striatal lesions that were significantly smaller within mutant caspase-1 mice than in littermate control mice. These results provide further evidence of a functional role for caspase-1 in both malonate- and 3-NP-mediated neurotoxin models of HD.
Animals↗
Frontal lobe dysfunction in progressive supranuclear palsy: evidence for oxidative stress and mitochondrial impairment.
Recent data from our laboratory have shown a regionally specific increase in lipid peroxidation in postmortem progressive supranuclear palsy (PSP) brain. To extend this finding, we measured activities of mitochondrial enzymes as well as tissue malondialdehyde (MDA) levels in postmortem superior frontal cortex (Brodmann's area 9; SFC) from 14 pathologically confirmed cases of PSP and 13 age-matched control brains. Significant decreases (-39%) in alpha-ketoglutarate dehydrogenase complex/glutamate dehydrogenase ratio and significant increases (+36%) in tissue MDA levels were observed in the SFC in PSP; no differences in complex I or complex IV activities were detected. Together, these results suggest that mitochondrial dysfunction and lipid peroxidation may underlie the frontal metabolic and functional deficits observed in PSP.
Aged↗
Mitochondria and the pathogenesis of ALS.
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Amyotrophic Lateral Sclerosis↗
Oxidative metabolism.
There is a large body of evidence showing both metabolic defects and oxidative damage in Alzheimer's disease. Studies of cybrid cell lines show reduced cytochrome oxidase. There is also substantial evidence for a defect in alpha-ketoglutarate dehydrogenase. It is therefore possible that therapeutic strategies to improve brain metabolism or ameliorate oxidative damage might be useful in treating Alzheimer's disease.
Alzheimer Disease↗
The role of mitochondria in the pathogenesis of neurodegenerative diseases.
A growing body of evidence indicates that mitochondrial dysfunction may play an important role in the pathogenesis of many neurodegenerative disorders. Because mitochondrial metabolism is not only the principal source of high energy intermediates, but also of free radicals, it has been suggested that inherited or acquired mitochondrial defects could be the cause of neuronal degeneration as a consequence of energy defects and oxidative damage. Mitochondrial respiratory chain dysfunction has been reported in association with primary mitochondrial DNA abnormalities, and also as a consequence of mutations in nuclear genes directly involved in mitochondrial functions, such as SURF1, frataxin, and paraplegin. Defects of oxidative phosphorylation and increased free radical production have also been observed in diseases that are not due to primary mitochondrial abnormalities. In these cases, the mitochondrial dysfunction is likely to be an epiphenomenon, which, nevertheless, could be of importance in precipitating a cascade of events leading to cell death. In either case, understanding the role of mitochondria in the pathogenesis of neurodegenerative diseases could be important for the development of therapeutic strategies in these disorders.
DNA, Mitochondrial↗
Partial deficiency of manganese superoxide dismutase exacerbates a transgenic mouse model of amyotrophic lateral sclerosis.
The pathogenesis of neuronal cell death as a consequence of mutations in copper/zinc superoxide dismutase (SOD1) associated with familial amyotrophic lateral sclerosis may involve oxidative damage and mitochondrial dysfunction. We examined whether crossing transgenic mice with the G93A SOD1 mutation with transgenic mice with a partial depletion of manganese superoxide dismutase (SOD2) would affect the disease phenotype. Compared with G93A mice alone, the mice with partial deficiency of SOD2 and the G93A SOD1 mutation showed a significant decrease in survival and an exacerbation of motor deficits detected by rotorod testing. There was a significant exacerbation of loss of motor neurons and substantia nigra dopaminergic neurons in the G93A mice with a partial deficiency of SOD2 compared with G93A mice at 110 days. Microvesiculation of large motor neurons was more prominent in the G93A mice with a partial deficiency of SOD2 compared with G93A mice at 90 days. These findings provide further evidence that both oxidative damage and mitochondrial dysfunction may play a role in the pathogenesis of motor neuron death associated with mutations in SOD1.
Amyotrophic Lateral Sclerosis↗
No difference in plasma or urinary F2-isoprostanes among patients with Huntington's disease or Alzheimer's disease and controls.
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Aged↗
Familial multisystem degeneration with parkinsonism associated with the 11778 mitochondrial DNA mutation.
OBJECTIVE: To investigate a family with maternally inherited, adult-onset multisystem degeneration including prominent parkinsonism to determine whether clinical features can result from a mitochondrial DNA (mtDNA) mutation. The parkinsonism was levodopa responsive and was associated with the loss of pigmented neurons in the substantia nigra in at least one patient. BACKGROUND: Mitochondrial dysfunction is hypothesized to play a role in late-onset neurodegenerative diseases including PD and AD. Mitochondrial genetic mutations are hypothesized to account for these defects, but attempts to identify specific mtDNA mutations have been inconclusive. METHODS: Clinical examinations, DNA sequencing, and restriction digestion and biochemical analyses were performed. RESULTS: Maternal relatives harbor a G-to-A missense mutation, heteroplasmic in some patients, at nucleotide position 11778 of the mitochondrial ND4 gene of complex I that converts a highly conserved arginine to a histidine. Sequencing of the entire mitochondrial genome in an affected family member reveals no other mutations likely to be pathogenic. This mutation has been identified previously only in families with Leber's hereditary optic neuropathy-a disorder also linked to complex I dysfunction but usually limited clinically to optic atrophy. CONCLUSIONS: These data reveal previously unsuspected clinical heterogeneity of the G11778A mutation, and suggest that an inherited mtDNA mutation can contribute to the development of adult-onset parkinsonism and multisystem degeneration.
Base Sequence↗
Detection of dopaminergic cell loss and neural transplantation using pharmacological MRI, PET and behavioral assessment.
We demonstrate the use of magnetic resonance imaging (MRI) for detection of neurotransmitter stimulation using the dopamine transporter ligands amphetamine and CFT (2beta-carbomethoxy-3beta-(4-fluorophenyl)tropane) as pharmacological challenges. We demonstrate that the unilateral loss of a hemodynamic response to either amphetamine or CFT challenge by unilateral 6-hydroxydopamine lesioning is restored by transplantation of fetal dopamine neurons in the striatum. The time course for the hemodynamic changes parallels the time courses for dopamine release, measured by prior microdialysis studies, and also for the rotational behavior in the unilaterally lesioned animals. Transplantation of the fetal cells results in hemodynamic time courses after CFT or amphetamine challenges at the graft site that are identical to those induced both before transplantation and on the intact contralateral side. The transplantation also results in complete behavioral recovery. The spatial extent of the dopaminergic recovery in the lesioned striatum is the same when measured using either PET of tracer levels of [11C]CFT binding or MRI. These results show great promise for the application of pharmacological MRI for application to studies of dopamine cell loss and potential recovery in Parkinson's disease.
Amphetamine↗
Oxidative damage to mitochondrial DNA in Huntington's disease parietal cortex.
Oxidative damage to DNA may play a role in both normal aging and in neurodegenerative diseases. Using a sensitive high-performance liquid chromatography (HPLC) assay, we examined concentrations of 8-hydroxy-2-deoxyguanosine (OH8dG) in mitochondrial DNA (mtDNA) isolated from frontal and parietal cerebral cortex and from cerebellum in 22 Huntington's disease (HD) patients and 15 age-matched normal controls. A significant increase in OH8dG in mtDNA of parietal cortex was found in HD patients as compared with controls, while there were no significant changes in frontal cortex or cerebellum. The present findings are consistent with regionally specific oxidative damage in HD, which may be a further evidence of a metabolic defect.
8-Hydroxy-2'-Deoxyguanosine↗
Increased nitrotyrosine immunoreactivity in substantia nigra neurons in MPTP treated baboons is blocked by inhibition of neuronal nitric oxide synthase.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces clinical, biochemical and neuropathologic changes reminiscent of those which occur in idiopathic Parkinson's disease. 7-Nitroindazole (7-NI) is a relatively selective inhibitor of the neuronal isoform of nitric oxide synthase. We previously demonstrated that administration of 7-NI is effective in blocking MPTP toxicity in both mice and baboons. This was suggested to be due to inhibition of the generation of peroxynitrite which can nitrate tyrosines. In the present study we found increased 3-nitrotyrosine immunoreactivity in the substantia nigra of MPTP treated baboons, which was blocked by coadministration of 7-NI. These findings provide further evidence that peroxynitrite may play a role in MPTP induced parkinsonism in baboons.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗