0000000000179765
AUTHOR
Heidrun Witan
Heterodimer formation of wild-type and amyotrophic lateral sclerosis-causing mutant Cu/Zn-superoxide dismutase induces toxicity independent of protein aggregation
Recent studies provide evidence that wild-type Cu/Zn-superoxide dismutase (SOD1(hWT)) might be an important factor in mutant SOD1-mediated amyotrophic lateral sclerosis (ALS). In order to investigate its functional role in the pathogenesis of ALS, we designed fusion proteins of two SOD1 monomers linked by a polypeptide. We demonstrated that wild-type-like mutants, but not SOD1(G85R) homodimers, as well as mutant heterodimers including SOD1(G85R)-SOD1(hWT) display dismutase activity. Mutant homodimers showed an increased aggregation compared with the corresponding heterodimers in cell cultures and transgenic Caenorhabditis elegans, although SOD1(G85R) heterodimers are more toxic in functiona…
Wild-type Cu/Zn superoxide dismutase (SOD1) does not facilitate, but impedes the formation of protein aggregates of amyotrophic lateral sclerosis causing mutant SOD1
Aggregation of Cu/Zn superoxide dismutase (SOD1) is a hallmark of a subset of familial amyotrophic lateral sclerosis (ALS) cases. The expression of wild-type SOD1 [SOD(hWT)] surprisingly exacerbates the phenotype of mutant SOD1 in vivo. Here we studied whether SOD1(hWT) may affect mutant SOD1 aggregation by employing fluorescence microscopy techniques combined with lifetime-based Förster resonance energy transfer (FRET). Only a very minor fraction of SOD1(hWT) was observed in aggregates induced by mutant SOD1(G37R), SOD1(G85R) or SOD1(G93C). Quite in contrast, co-expression of SOD(hWT) reduced the amount of mutant SOD1 in the aggregate fraction. Furthermore, we did not detect endogenous mou…
One Enzyme, Two Functions
The human enzyme paraoxonase-2 (PON2) has two functions, an enzymatic lactonase activity and the reduction of intracellular oxidative stress. As a lactonase, it dominantly hydrolyzes bacterial signaling molecule 3OC12 and may contribute to the defense against pathogenic Pseudomonas aeruginosa. By its anti-oxidative effect, PON2 reduces cellular oxidative damage and influences redox signaling, which promotes cell survival. This may be appreciated but also deleterious given that high PON2 levels reduce atherosclerosis but may stabilize tumor cells. Here we addressed the unknown mechanisms and linkage of PON2 enzymatic and anti-oxidative function. We demonstrate that PON2 indirectly but specif…
Differential Promotion of Glutamate Transporter Expression and Function by Glucocorticoids in Astrocytes from Various Brain Regions
Steroids that activate glucocorticoid receptors (GRs) and mineralocorticoid receptors have important regulatory effects on neural development, plasticity, and the body's stress response. Here, we investigated the role of corticosteroids in regulating the expression of the glial glutamate transporters glial glutamate transporter-1 (GLT-1) and glutamate-aspartate transporter (GLAST) in rat primary astrocytes. The synthetic glucocorticoid dexamethasone provoked a marked increase of GLT-1 transcription and protein levels in cortical astrocytes, whereas GLAST expression remained unaffected. Up-regulation of GLT-1 expression was accompanied by an enhanced glutamate uptake, which could be blocked …