The quality of life of ALS patients has substantially improved in the past decade from better nutrition, respiratory support and a variety of complementary and alternative medicines (CAM). CAM for ALS patients is well accepted by the traditional medical community. Our long-term goal is to find a combination of therapeutic actions to slow the progressive death of motor neurons that defines ALS, turning this fatal disease into a chronic condition resembling post-polio syndrome. An important clue came from discovering mutations to the antioxidant copper, zinc superoxide dismutase cause 2-3% of ALS patients. We found that the loss of zinc from SOD, which is favored by the mutations, is toxic to motor neurons by increasing nitrative stress, suggesting zinc status could link the 2% familial SOD patients with the remaining 98% of ALS patients. Our research has also shown that nitrative stress in astrocytes surrounding motor neurons contributes to the progressive death of motor neurons. Expression of ALS-mutant SODs in transgenic mice and rats is now widely used to study the effects of both traditional as well as CAM therapies on survival. With a better understanding of how SOD malfunctions to cause ALS, we have identified several novel CAM antioxidant therapies that could modulate the progression of ALS. Using a combination of cell culture and microanalytical methods of spinal cord from transgenic rats, we will characterize the ability of CAM therapies to modulate disease progression in these animals.
Our first aim i s to determine whether zinc can slow the progression of ALS in transgenic SOD rats and whether heavy metal chelation therapy unintentionally may accelerate ALS by removing zinc.
Our second aim will characterize whether the depletion of ascorbate by zinc deficient SOD makes the spinal cord vulnerable to a-tocopherol deficiencies.
Our final aim will characterize whether lipoic acid can ameliorate the effects of a-tocopherol deficiency or reduce the toxic effects of SOD in aging rats. Our proposed studies will provide a mechanistic basis for examining how CAM antioxidant therapies can be coordinated to modulate the course of ALS. PERFORMANCE SITE(
|Williams, Jared R; Trias, Emiliano; Beilby, Pamela R et al. (2016) Copper delivery to the CNS by CuATSM effectively treats motor neuron disease in SOD(G93A) mice co-expressing the Copper-Chaperone-for-SOD. Neurobiol Dis 89:1-9|
|Thomas, Nicholas O; Shay, Kate P; Kelley, Amanda R et al. (2016) Glutathione maintenance mitigates age-related susceptibility to redox cycling agents. Redox Biol 10:45-52|
|Smith, Eric J; Shay, Kate P; Thomas, Nicholas O et al. (2015) Age-related loss of hepatic Nrf2 protein homeostasis: Potential role for heightened expression of miR-146a. Free Radic Biol Med 89:1184-91|
|Zhang, Wei-Jian; Frei, Balz (2015) Astragaloside IV inhibits NF- ? B activation and inflammatory gene expression in LPS-treated mice. Mediators Inflamm 2015:274314|
|Keith, Dove; Finlay, Liam; Butler, Judy et al. (2014) Lipoic acid entrains the hepatic circadian clock and lipid metabolic proteins that have been desynchronized with advanced age. Biochem Biophys Res Commun 450:324-9|
|Wei, Hao; Zhang, Wei-Jian; Leboeuf, Renee et al. (2014) Copper induces--and copper chelation by tetrathiomolybdate inhibits--endothelial activation in vitro. Redox Rep 19:40-8|
|Viera, Liliana; Radmilovich, Milka; Vargas, Marcelo R et al. (2013) Temporal patterns of tyrosine nitration in embryo heart development. Free Radic Biol Med 55:101-8|
|Gandelman, Mandi; Levy, Mark; Cassina, Patricia et al. (2013) P2X7 receptor-induced death of motor neurons by a peroxynitrite/FAS-dependent pathway. J Neurochem 126:382-8|
|Rhoads, Timothy W; Williams, Jared R; Lopez, Nathan I et al. (2013) Using theoretical protein isotopic distributions to parse small-mass-difference post-translational modifications via mass spectrometry. J Am Soc Mass Spectrom 24:115-24|
|Franco, Maria Clara; Ye, Yaozu; Refakis, Christian A et al. (2013) Nitration of Hsp90 induces cell death. Proc Natl Acad Sci U S A 110:E1102-11|
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