Wang XD , Zhu MW , Shan D , Wang SY , Yin X , Yang YQ , Wang TH , Zhang CT , Wang Y , Liang WW , Zhang J , Jiang HZ , Dong GT , Jiang HQ , Qi Y , Feng HL .

　　DNA Repair (Amst). 2018 Dec 21. pii: S1568-7864(18)30164-2. doi: 10.1016/j.dnarep.2018.12.005. [Epub ahead of print]

　　Abstract

　　Increasing evidence indicates that DNA damage and p53 activation play major roles in the pathological process of motor neuron death in amyotrophic lateral sclerosis (ALS). Human SpeedyA1 (Spy1), a member of the Speedy/Ringo family, enhances cell proliferation and promotes tumorigenesis. Further studies have demonstrated that Spy1 promotes cell survival and inhibits DNA damage-induced apoptosis. We showed that the Spy1 expression levels were substantially decreased in ALS motor neurons compared with wild-type controls both in vivo and in vitro by qRT-PCR, western blotting, and Immunoassay tests. In addition, we established that over-expression of human SOD1 mutant G93A led to a decreased expression of Spy1. Furthermore, DNA damage response was activated in SOD1G93A-transfected cells (mSOD1 cells). Moreover, decreased Spy1 expression reduced cell viability and further activated the DNA damage response in mSOD1 cells. In contrast, increased Spy1 expression improved cell viability and inhibited the DNA damage response in mSOD1 cells. These results suggest that Spy1 plays a protective role in ALS motor neurons. Importantly, these findings provide a novel direction for therapeutic options for patients with ALS as well as for trial designs, such as investigating the role of oncogenic proteins in ALS.

　　Copyright © 2018 Elsevier B.V. All rights reserved.

　　KEYWORDS:

　　(SOD1); Amyotrophic lateral sclerosis (ALS); Cu/Zn superoxide dismutase 1; DNA damage response; SpeedyA1 (Spy1)