Mitochondria are particularly vulnerable to oxidative stress, and mitochondrial swelling and vacuolization are among the earliest pathologic features found in two strains of transgenic amyotrophic lateral sclerosis (ALS) mice with SOD1 mutations. Mice with the G93A human SOD1 mutation have altered electron transport enzymes, and expression of the mutant enzyme in vitro results in a loss of mitochondrial membrane potential and elevated cytosolic calcium concentration. Mitochondrial dysfunction may lead to ATP depletion, which may contribute to cell death. If this is true, then buffering intracellular energy levels could exert neuroprotective effects. Creatine kinase and its substrates creatine and phosphocreatine constitute an intricate cellular energy buffering and transport system connecting sites of energy production (mitochondria) with sites of energy consumption, and creatine administration stabilizes the mitochondrial creatine kinase and inhibits opening of the mitochondrial transition pore. We found that oral administration of creatine produced a dose-dependent improvement in motor performance and extended survival in G93A transgenic mice, and it protected mice from loss of both motor neurons and substantia nigra neurons at 120 days of age. Creatine administration protected G93A transgenic mice from increases in biochemical indices of oxidative damage. Therefore, creatine administration may be a new therapeutic strategy for ALS.

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...

The perineuronal net forms the extracellular matrix of many neurons in the CNS, surrounding neuron cell bodies and proximal dendrites in a mesh-like structure with open "holes" at the sites of synaptic contacts. The perineuronal net is first detected late in development, approximately coincident with the transformation of the CNS from an environment conducive to neuronal growth and motility to one that is restrictive, suggesting a role for the perineuronal net in this developmental transition. Perineuronal nets show a great degree of molecular heterogeneity. Using monoclonal antibodies Cat-301, Cat-315, and Cat-316, we have shown previously that although all antibodies recognize chondroitin sulfate proteoglycans of similar sizes, each antibody recognizes perineuronal nets on distinct but overlapping sets of neurons in the adult cat CNS. An understanding of the heterogeneity demonstrated by these antibodies is critical to understanding the organization and function of perineuronal nets. Using aggrecan knock-out mice (cmd), we have now determined that all three antibodies recognize aggrecan. Chemical and enzymatic deglycosylation show that the differences revealed by the three antibodies arise from differential glycosylation of aggrecan. We further demonstrate that aggrecan mRNA is expressed relatively late in development and that neurons themselves are likely the predominant cellular sites of aggrecan expression. This work indicates that neurons can directly regulate the composition of their extracellular matrix by regulated synthesis and differential glycosylation of aggrecan in a cell type-specific manner. These results have important implications for the role of regulated microheterogeneity of glycosylation in the CNS.