کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
3070147 | 1580726 | 2008 | 9 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Gain of interaction of ALS-linked G93A superoxide dismutase with cytosolic malate dehydrogenase Gain of interaction of ALS-linked G93A superoxide dismutase with cytosolic malate dehydrogenase](/preview/png/3070147.png)
Protein interactions of the Amyotrophic Lateral Sclerosis (ALS)-linked copper–zinc superoxide dismutase (hSOD1) G93A mutation were studied using a fluorescence resonance energy transfer (FRET) based screening system. The FRET results confirmed by pull-down immunoprecipitation indicated “gain-of-interaction” of the G93A-hSOD1 mutant with cytosolic malate dehydrogenase (cytMDH)—a key enzyme in the malate–aspartate shuttle which is vital to neurons. Furthermore, cytMDH mRNA expression was upregulated in G93A-hSOD1 expressing cells but endogenous cytMDH enzymatic activity was not enhanced, not even with exogenously added-on enzyme. Consistent with inhibition of the malate–aspartate shuttle, G93A-hSOD1 had lower malate and higher lactate levels compared to non-induced or Wild-Type-hSOD1 expressing cells. Mitochondrial NADH/NAD+ ratio is also elevated. Malate–aspartate shuttle dysfunction may explain the damage to neurons and the vulnerability to impairments of glycolytic pathways in ALS and provide a new target for the development of potential therapies.
Journal: Neurobiology of Disease - Volume 32, Issue 1, October 2008, Pages 133–141