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, 46 (6), 6299-6309

Lithium Facilitates Removal of Misfolded Proteins and Attenuated Faulty Interaction Between Mutant SOD1 and p-CREB (Ser133) Through Enhanced Autophagy in Mutant hSOD1 G93A Transfected Neuronal Cell Lines

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Lithium Facilitates Removal of Misfolded Proteins and Attenuated Faulty Interaction Between Mutant SOD1 and p-CREB (Ser133) Through Enhanced Autophagy in Mutant hSOD1 G93A Transfected Neuronal Cell Lines

Xiang Yin et al. Mol Biol Rep.

Abstract

Abnormally protein aggregation and deposition are key pathological features of ALS, which may related with dysfunctional cellular autophagy. In the current study, we found that, compared with wtSOD1 cells, serum starvation treatment resulted in significant higher percentage of apoptosis in mutSOD1 cells; Lithium treatment exerted protection for those mutSOD1 cells, with decreased GFP-tagged mutant SOD1 protein aggregates deposition; Whereas, pre-treatment with Baf or 3-MA (autophagy inhibitors) blocked protection of lithium for mutant SOD1 cells, and induced increased GFP-tagged mutant SOD1 protein aggregation. Further, Western blots results showed that lithium treatment led to decrease of mutant hSOD1 protein levels in both Triton X-100 soluble and Triton X-100 insoluble fraction of mutSOD1 cells. Besides, improper binding of mutant SOD1 proteins' aggregates with p-CREB (Ser133) (transcription factor) in mutSOD1 cells were demonstrated; whereas lithium treatment attenuated this fault interaction. In conclusion, our results showed that, in mutSOD1 cells, mutSOD1 protein aggregates were related with abnormal autophagic regulation. Lithium treatment could induce autophagy and enhance clearance of protein aggregates, further exerting protection on mutSOD1 cells. More importantly, we uncovered another distinct pathological role of mutSOD1 protein aggregates, that is abnormal binding with p-CREB (Ser133), an important transcription factor, which may play crucial role in the PI3K-Akt-CREB-AEG-1 signaling pathway.

Keywords: Amyotrophic lateral sclerosis (ALS); Apoptosis; Autophagy; Lithium; Protein aggregation.

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