Molecular chaperones, ubiquitin ligases and proteasome impairment have been implicated in several neurodegenerative diseases, including Alzheimer's and Parkinson's disease, which are characterized by accumulation of abnormal protein aggregates (e.g. tau and alpha-synuclein respectively). Here we report that CHIP, an ubiquitin ligase that interacts directly with Hsp70/90, induces ubiquitination of the microtubule associated protein, tau. CHIP also increases tau aggregation. Consistent with this observation, diverse of tau lesions in human postmortem tissue were found to be immunopositive for CHIP. Conversely, induction of Hsp70 through treatment with either geldanamycin or heat shock factor 1 leads to a decrease in tau steady-state levels and a selective reduction in detergent insoluble tau. Furthermore, 30-month-old mice overexpressing inducible Hsp70 show a significant reduction in tau levels. Together these data demonstrate that the Hsp70/CHIP chaperone system plays an important role in the regulation of tau turnover and the selective elimination of abnormal tau species. Hsp70/CHIP may therefore play an important role in the pathogenesis of tauopathies and also represents a potential therapeutic target.
The etiology of the selective neuronal death that occurs in Huntington's disease (HD) is unknown. Several lines of evidence implicate the involvement of energetic defects and oxidative damage in the disease process, including a recent study that demonstrated an interaction between huntingtin protein and the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Using spectrophotometric assays in postmortem brain tissue, we found evidence of impaired oxidative phosphorylation enzyme activities restricted to the basal ganglia in HD brain, while enzyme activities were unaltered in three regions relatively spared by HD pathology (frontal cortex, parietal cortex, and cerebellum). Citrate synthase-corrected complex II-III activity was markedly reduced in both HD caudate (-29%) and putamen (-67%), and complex IV activity was reduced in HD putamen (-62%). Complex I and GAPDH activities were unaltered in all regions examined. We also measured levels of the oxidative damage product 8-hydroxydeoxyguanosine (OH8dG) in nuclear DNA, and superoxide dismutase (SOD) activity. OH8dG levels were significantly increased in HD caudate. Cytosolic SOD activity was slightly reduced in HD parietal cortex and cerebellum, whereas particulate SOD activity was unaltered in these regions. These results further support a role for metabolic dysfunction and oxidative damage in the pathogenesis of HD.
Mitochondria-produced reactive oxygen species (ROS) are thought to contribute to cell death caused by a multitude of pathological conditions. The molecular sites of mitochondrial ROS production are not well established but are generally thought to be located in complex I and complex III of the electron transport chain. We measured H 2 O 2 production, respiration, and NADPH reduction level in rat brain mitochondria oxidizing a variety of respiratory substrates. Under conditions of maximum respiration induced with either ADP or carbonyl cyanide p-trifluoromethoxyphenylhydrazone, ␣-ketoglutarate supported the highest rate of H 2 O 2 production. In the absence of ADP or in the presence of rotenone, H 2 O 2 production rates correlated with the reduction level of mitochondrial NADPH with various substrates, with the exception of ␣-ketoglutarate. Isolated mitochondrial ␣-ketoglutarate dehydrogenase (KGDHC) and pyruvate dehydrogenase (PDHC) complexes produced superoxide and H 2 O 2 . NAD ϩ inhibited ROS production by the isolated enzymes and by permeabilized mitochondria. We also measured H 2 O 2 production by brain mitochondria isolated from heterozygous knock-out mice deficient in dihydrolipoyl dehydrogenase (Dld). Although this enzyme is a part of both KGDHC and PDHC, there was greater impairment of KGDHC activity in Dld-deficient mitochondria. These mitochondria also produced significantly less H 2 O 2 than mitochondria isolated from their littermate wild-type mice. The data strongly indicate that KGDHC is a primary site of ROS production in normally functioning mitochondria.
Coenzyme Q 10 is an essential cofactor of the electron transport chain as well as a potent free radical scavenger in lipid and mitochondrial membranes. Feeding with coenzyme Q 10 increased cerebral cortex concentrations in 12-and 24-month-old rats. In 12-month-old rats administration of coenzyme Q 10 resulted in significant increases in cerebral cortex mitochondrial concentrations of coenzyme Q 10 . Oral administration of coenzyme Q 10 markedly attenuated striatal lesions produced by systemic administration of 3-nitropropionic acid and significantly increased life span in a transgenic mouse model of familial amyotrophic lateral sclerosis. These results show that oral administration of coenzyme Q 10 increases both brain and brain mitochondrial concentrations. They provide further evidence that coenzyme Q 10 can exert neuroprotective effects that might be useful in the treatment of neurodegenerative diseases.Coenzyme Q is an essential cofactor in the electron transport chain where it accepts electrons from complex I and II (1-3). Coenzyme Q also serves as an important antioxidant in both mitochondria and lipid membranes (4, 5). Coenzyme Q, which also is known as ubiquinone, is a lipid-soluble compound composed of a redox active quinoid moiety and a hydrophobic ''tail.'' The predominant form of coenzyme Q in humans is coenzyme Q 10 , which contains 10 isoprenoid units in the tail, whereas the predominant form in rodents is coenzyme Q 9 , which has nine isoprenoid units in the tail. Coenzyme Q is soluble and mobile in the hydrophobic core of the phospholipid bilayer of the inner membrane of the mitochondria where it transfers electrons one at a time to complex III of the electron transport chain.There has been considerable interest in the use of coenzyme Q 10 for the treatment of mitochondrial disorders. Several reports found both clinical and biochemical improvement in patients with mitochondrial disorders (6-10). If defects in energy metabolism and oxidative damage play a role in the pathogenesis of neurodegenerative diseases (11, 12), then treatment with coenzyme Q 10 could exert beneficial therapeutic effects. We previously showed that oral administration of coenzyme Q 10 significantly attenuated lesions produced by intrastriatal administration of malonate in rats, as well as malonate-induced depletions of ATP and increases in lactate concentrations (13). In the present study, we examined the effects of oral administration of coenzyme Q 10 on brain and brain mitochondrial concentrations. We examined both oxidized and reduced coenzyme Q 10 levels because the latter is the form that exerts antioxidant effects (4, 5). We examined neuroprotective effects against striatal lesions produced by systemic administration of 3-nitropropionic acid (3-NP) and survival in a transgenic animal model of familial amyotrophic lateral sclerosis (ALS). MATERIALS AND METHODSStudies of coenzyme Q 10 were carried out in male SpragueDawley rats. Coenzyme Q 10 powder (Vitaline Formulas, Ashland, OR) was formulated in rat chow (Agw...
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