Increased SIRT3 combined with PARP inhibition rescues motor function of SBMA mice.

Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease with substantial mitochondrial and metabolic dysfunctions. SBMA is caused by polyglutamine (polyQ) expansion in the androgen receptor (AR). Activating or increasing the NAD+-dependent deacetylase, SIRT3, reduced oxidative stress and death of cells modeling SBMA. However, increasing diminished SIRT3 in AR100Q mice failed to reduce acetylation of the SIRT3 target/antioxidant, SOD2, and had no effect on increased total acetylated peptides in quadriceps. Yet, overexpressing SIRT3 resulted in a trend of motor recovery, and corrected TCA cycle activity by decreasing acetylation of SIRT3 target proteins. We sought to boost blunted SIRT3 activity by replenishing diminished NAD+ with PARP inhibition. Although NAD+ was not affected, overexpressing SIRT3 with PARP inhibition fully restored hexokinase activity, correcting the glycolytic pathway in AR100Q quadriceps, and rescued motor endurance of SBMA mice. These data demonstrate that targeting metabolic anomalies can restore motor function downstream of polyQ-expanded AR

Increased SIRT3 Combined With PARP Inhibition Rescues Motor Function of SBMA Mice

Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease with substantial mitochondrial and metabolic dysfunctions. SBMA is caused by polyglutamine (polyQ) expansion in the androgen receptor (AR). Activating or increasing the NAD+-dependent deacetylase, SIRT3, reduced oxidative stress and death of cells modeling SBMA. However, increasing diminished SIRT3 in AR100Q mice failed to reduce acetylation of the SIRT3 target/antioxidant, SOD2, and had no effect on increased total acetylated peptides in quadriceps. Yet, overexpressing SIRT3 resulted in a trend of motor recovery, and corrected TCA cycle activity by decreasing acetylation of SIRT3 target proteins. We sought to boost blunted SIRT3 activity by replenishing diminished NAD+ with PARP inhibition. Although NAD+ was not affected, overexpressing SIRT3 with PARP inhibition fully restored hexokinase activity, correcting the glycolytic pathway in AR100Q quadriceps, and rescued motor endurance of SBMA mice. These data demonstrate that targeting metabolic anomalies can restore motor function downstream of polyQ-expanded AR

Increased SIRT3 combined with PARP inhibition rescues motor function of SBMA mice

Summary: Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease with substantial mitochondrial and metabolic dysfunctions. SBMA is caused by polyglutamine (polyQ) expansion in the androgen receptor (AR). Activating or increasing the NAD+-dependent deacetylase, SIRT3, reduced oxidative stress and death of cells modeling SBMA. However, increasing diminished SIRT3 in AR100Q mice failed to reduce acetylation of the SIRT3 target/antioxidant, SOD2, and had no effect on increased total acetylated peptides in quadriceps. Yet, overexpressing SIRT3 resulted in a trend of motor recovery, and corrected TCA cycle activity by decreasing acetylation of SIRT3 target proteins. We sought to boost blunted SIRT3 activity by replenishing diminished NAD+ with PARP inhibition. Although NAD+ was not affected, overexpressing SIRT3 with PARP inhibition fully restored hexokinase activity, correcting the glycolytic pathway in AR100Q quadriceps, and rescued motor endurance of SBMA mice. These data demonstrate that targeting metabolic anomalies can restore motor function downstream of polyQ-expanded AR

The Competition Effects of Lookalike Private Label Products

This paper considers the competition effects of lookalike products, which seek to mimic the packaging, design and appearance of leading brands. Such products, most notable in the fast-moving-consumer-goods (FMCG) sector, are particularly associated with items promoted by retail organizations as part of their private-label programmes. The market power and control over the supply chain which the major retailers now enjoy means that by developing lookalike products they may have the opportunity to exploit unfairly and anti-competitively the image and goodwill that brand manufacturers have developed through careful and continual product and marketing investment. This, in turn, could distort the way and the extent to which manufacturers compete, enhance retailer control over the supply chain. In the process, this could undermine manufacturer branded goods which smaller retailers traditionally rely on, thus weakening their competitive position and resulting in further concentration of retail markets and less choice of store types and product varieties for consumers. The continuing absence of a rapid and effective legal remedy to prevent the rewards from brand investment being misappropriated by imitators means that such action will likely continue, with the upshot that manufacturer and retailer competition may be distorted to the detriment of consumer welfare and the public interest