Amyotrophic lateral sclerosis (ALS) caused by mutation of superoxide dismutase 1 (SOD1), affects various cellular processes and results in the death of motor neurons with fatal defects. Currently, several neurological disorders associated with DNA damage are known to directly induce neurodegenerative diseases. In this research, we found that cytoplasmic restriction of SOD1G93A, which inhibited the nucleic translocation of SOD1WT, was directly related to increasing DNA damage in SOD1- mutated ALS disease. Our study showed that nucleic transport of DNA repair- processing proteins, such as p53, APEX1, HDAC1, and ALS- linked FUS were interfered with under increased endoplasmic reticulum (ER) stress in the presence of SOD1G93A. During aging, the unsuccessful recognition and repair process of damaged DNA, due to the mislocalized DNA repair proteins might be closely associated with the enhanced susceptibility of DNA damage in SOD1- mutated neurons. In addition, the co-expression of protein disulphide isomerase (PDI) directly interacting with SOD1 protein in neurons enhances the nucleic transport of cytoplasmic- restricted SOD1G93A. Therefore, our results showed that enhanced DNA damage by SOD1 mutation-induced ALS disease and further suggested that PDI could be a strong candidate molecule to protect neuronal apoptosis by reducing DNA damage in ALS disease.

Kim DH, et al. J Korean Med Sci. 2014 Dec;29(12):1604-1609. http://dx.doi.org/10.3346/jkms.2014.29.12.1604

Recently, SGI-1027, a well-known inhibitor of DNA-methyl transferases (DNMTs), was reported to effectively reduce formation of pathogenic PrP^Sc in prion-infected cells. Herein, we confirm the elimination of PrP^Sc in chronic wasting disease (CWD) prion-infected neurons by SGI-1027, and pinpoint the binding region of human prion protein to SGI-1027. SGI-1027 is broadly functional against various prion disease types, including human prions. Previously, the inhibitory effects of SGI-1027 on DNMT function is well tested in various cell culture models. While neither treatment with a DNMTs enhancer S-adenosyl-L-methionine (SAM), nor with their inhibitor, 5-azacytidine, prevented PrP^Sc propagation, SGI-1027 did. Our study suggest that the anti-prion effects of SGI-1027 are a result of its direct interaction with PrP^C, which effectively interferes with the pathogenic conformational change of PrP^C to PrP^Sc. We conclude that SGI-1027 driven suppression of pathogenic PrP^Sc is independent of DNMT.

Недавно показано, что SGI-1027, хорошо известный ингибитор ДНК-метилтрансферазы (DNMT), эффективно снижает образования патогенного прионного белка PrP^Sc в инфицированных прионом клетках. Теперь мы подтвердили, что в нейронах, инфицированных прионом болезни хронического истощения (CWD), под действием SGI-1027 происходит элиминация PrP^Sc, и точно определили область связывания прионного белка человека с SGI-1027. SGI-1027 широко используется против различных типов прионных заболеваний, включая вызванные прионами человека. Нами показано, что SGI-1027 предотвращает распространение PrP^Sc, в то время как ни обработка энхансером DNMTs S-аденозил-L-метионином (SAM), ни их ингибитором 5-азацитидином не влияют на формирование патогена. Установлено, что антиприонная активность SGI-1027 есть результат его прямого взаимодействия с PrP^C, которое и предотвращает конформационные изменения PrP^C, приводящие к формированию патогенного PrP^Sc. На основании полученных результатов сделан вывод, что элиминация патогенного PrP^Sc под действием SGI-1027 не зависит от DNMT.