Browsing by Subject "Superoxide Dismutase"
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Item Behavioral, Neurochemical, and Histological Characterization of Mice Deficient for Parkin, DJ-1, and Antioxidant Proteins(2011-08-10) Seamans, Katherine Webster; Goldberg, Matthew S.Parkinson’s disease is a progressive neurodegenerative disease characterized by a loss of dopaminergic neurons in the substantia nigra. The cause of Parkinson’s disease remains uncertain, however, evidence implicates mitochondrial dysfunction and oxidative stress with selective vulnerability of dopaminergic neurons. Although most cases of Parkinson’s disease are sporadic, 5-10% of cases are caused by mutations in a single gene. Loss-of-function mutations in parkin and DJ-1 were the first to be linked to recessively inherited parkinsonism. Surprisingly, mice bearing similar loss-of-function mutations in parkin and DJ-1 do not show age-dependent loss of nigral dopaminergic neurons or depletion of dopamine in the striatum. Although the normal cellular functions of Parkin and DJ-1 remain unclear, we hypothesized that Parkin and DJ-1 protect cells from oxidative stress and that loss-of-function mutations in these genes cause neurodegeneration in Parkinson’s disease by rendering cells more sensitive to mitochondrial dysfunction and oxidative stress. We crossed mice deficient for Parkin and DJ-1 with mice deficient for the major mitochondrial antioxidant protein Mn-superoxide dismutase or Cu/Zn-superoxide dismutase. Previous studies have shown that mice with reduced levels of Cu/Zn-superoxide dismutase or Mn-superoxide dismutase are more sensitive to dopaminergic neurotoxins whereas mice with increased levels of superoxide dismutase are more resistant to dopaminergic neurotoxins. We predicted that reducing levels of antioxidant proteins in parkin-/-DJ-1-/- mice would result in age-dependent nigral cell loss, striatal dopamine depletion or behavioral abnormalities. Characterization of these mice for behavioral abnormalities, neurotransmitter defects and neuropathology, revealed significant behavioral abnormalities in the mutant mice even in the absence of significant changes to dopamine levels in the striatum, dopamine receptor density, or dopaminergic neuron numbers. Aged parkin-/-DJ-1-/- and Mn-superoxide dismutase triple deficient mice have a surprising enhanced rotorod performance without the presence of an anxiety phenotype or hyperactivity. Cu/Zn-superoxide dismutase and Mn-superoxide dismutase triple deficient mice have elevated levels of dopamine in the striatum, however none of the mice present with nigral cell loss. Levels of D1-like and D2-like dopamine receptors in the striatum were unchanged. It is evident from our studies that on a parkin/DJ-1 null background, additional loss of major antioxidant proteins does not lead to a progressive loss of dopaminergic neurons in mice.Item A Role for BDNF-Trkb Signaling in the Modulation of Superoxide Dismutase-1 Expression(2014-04-15) Day, Cameron E.; Elliott, Jeffrey L.; Thomas, Philip J.; Cobb, Melanie H.; Kavalali, Ege T.Superoxide dismutase-1 (SOD1) has been implicated in the pathogenesis of familial amyotrophic lateral sclerosis (fALS), a degenerative motor neuron disease more commonly known as Lou Gehrig’s disease. The mechanism by which it causes degeneration and the extent of its involvement are currently unknown, although the present consensus is that a toxic gain-of-function mutation is involved. Our lab has previously demonstrated, via a cDNA expression screen, that the TrkB receptor and the guanine nucleotide exchange factor, RasGRF-1, modulate SOD1 expression at the protein level, suggesting that cell signaling pathways associated with TrkB signaling are involved in regulating the expression of SOD1. Overexpressing these proteins for long or ‘chronic’ time periods of 24-48 hours in a motor neuron-like cell line lead to a significant decrease in SOD1 protein levels. Subsequent experiments using TrkB mutants and pharmacological inhibitors of pathways known to be associated with TrkB revealed that the kinase activity of the receptor is necessary and that partial TrkB signaling is sufficient for suppression. Conversely, treatment with brain-derived neurotrophic factor (BDNF), an activator of this pathway, over shorter or ‘acute’ time periods increased SOD1 protein levels. Further analyses using qPCR, a human SOD1 promoter Lucifersase assay, and inhibitors of the proteasome and translation machinery provide evidence that in both the acute and chronic phase, BDNF-TrkB signaling is modulating SOD1 expression at the level of translation. Taken as a whole, these data demonstrate that BDNF-TrkB signaling is involved in the regulation of SOD1 expression via translation and that the expression pattern of SOD1 is bi-phasic in response to the duration of the stimulus. These findings may have implications for therapeutic modification of mutant SOD1 levels in ALS patients.