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- W4246090908 abstract "Abstract Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of upper and lower motor neurons. The exact mechanisms underlying motor neuron death in ALS are still not fully understood, but a growing body of evidence indicates that inflammatory could accentuate disease severity and accelerate disease progression. Currently, no neuroprotective strategies have effectively prevented the progression of this disease. Methods : IF, western blotting and RT-PCR were used to analyze the expression of PAK4 in vitro and in vivo models of ALS. We examined PAK4 function in ALS and the underlying mechanism by cell transfection, intraspinally injection of LV-PAK4 in hSOD1 G93A mice, flow cytometry, TUNEL staining, IF and western blotting. Results: Here, we observed that the expression and activity of PAK4 significantly decreased in hSOD1 G93A -related cell and mouse models of ALS. In hSOD1 G93A mice，the expression of PAK4 began to decrease at early-symptom stages of the disease. PAK4 silencing increased degeneration of motor neurons (NSC34 cells) and suppressed the CREB pathway. Overexpression of PAK4 protected motor neurons from hSOD1 G93A -induced degeneration by increasing the levels and transcriptional activity of CREB. The neuroprotective effect of PAK4 was markedly inhibited by compound 3i, a specific CREB inhibitor. In hSOD1 G93A -linked cell and mice, the CREB pathway, as the downstream target of decreased PAK4, was inhibited, and cell apoptosis increased. We also found that the expression of PAK4 was negatively regulated by miR-9-5p, and the miR-9-5p levels were upregulated in ALS. In vivo experiments revealed that PAK4 overexpression in the spinal neurons of hSOD1 G93A mice suppressed motor neuron degeneration, prolonged survival and promoted the CREB pathway. Conclusion: These results indicate that PAK4 plays a protective role for motor neurons by targeting CREB, suggesting it may be a useful therapeutic target in ALS." @default.
- W4246090908 created "2022-05-12" @default.
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- W4246090908 date "2020-10-20" @default.
- W4246090908 modified "2023-10-16" @default.
- W4246090908 title "PAK4 Suppresses Motor Neuron Degeneration in hSOD1G93A -Linked ALS Cell and Rat Models" @default.
- W4246090908 doi "https://doi.org/10.21203/rs.3.rs-93482/v1" @default.
- W4246090908 hasPublicationYear "2020" @default.
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