SUMOylation of Alpha-Synuclein Influences on Alpha-Synuclein Aggregation Induced by Methamphetamine
Methamphetamine (METH) is an illegal and widely abused psychoactive stimulant. METH abusers are at high risk of neurodegenerative disorders, including Parkinson’s disease (PD). Previous studies have demonstrated that METH causes alpha-synuclein (α-syn) aggregation in the both laboratory animal and h...
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doaj-275229488962438fbdc41878447faaa02020-11-24T21:17:49ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022018-08-011210.3389/fncel.2018.00262380942SUMOylation of Alpha-Synuclein Influences on Alpha-Synuclein Aggregation Induced by MethamphetamineLin-nan Zhu0Hong-hua Qiao1Ling Chen2Le-ping Sun3Jia-liang Hui4Yong-ling Lian5Wei-bing Xie6Jiu-yang Ding7Jiu-yang Ding8Yun-le Meng9Bo-feng Zhu10Ping-ming Qiu11School of Forensic Medicine, Southern Medical University, Guangzhou, ChinaSchool of Forensic Medicine, Southern Medical University, Guangzhou, ChinaSchool of Forensic Medicine, Southern Medical University, Guangzhou, ChinaSchool of Forensic Medicine, Southern Medical University, Guangzhou, ChinaFirst Clinical Medical College, Southern Medical University, Guangzhou, ChinaSchool of Forensic Medicine, Southern Medical University, Guangzhou, ChinaSchool of Forensic Medicine, Southern Medical University, Guangzhou, ChinaSchool of Forensic Medicine, Southern Medical University, Guangzhou, ChinaDepartment of Anatomy, Zunyi Medical College, Zunyi, ChinaSchool of Forensic Medicine, Southern Medical University, Guangzhou, ChinaSchool of Forensic Medicine, Southern Medical University, Guangzhou, ChinaSchool of Forensic Medicine, Southern Medical University, Guangzhou, ChinaMethamphetamine (METH) is an illegal and widely abused psychoactive stimulant. METH abusers are at high risk of neurodegenerative disorders, including Parkinson’s disease (PD). Previous studies have demonstrated that METH causes alpha-synuclein (α-syn) aggregation in the both laboratory animal and human. In this study, exposure to high METH doses increased the expression of α-syn and the small ubiquitin-related modifier 1 (SUMO-1). Therefore, we hypothesized that SUMOylation of α-syn is involved in high-dose METH-induced α-syn aggregation. We measured the levels of α-syn SUMOylation and these enzymes involved in the SUMOylation cycle in SH-SY5Y human neuroblastoma cells (SH-SY5Y cells), in cultures of C57 BL/6 primary mouse neurons and in brain tissues of mice exposure to METH. We also demonstrated the effect of α-syn SUMOylation on α-syn aggregation after METH exposure by overexpressing the key enzyme of the SUMOylation cycle or silencing SUMO-1 expression in vitro. Then, we make introduced mutations in the major SUMOylation acceptor sites of α-syn by transfecting a lentivirus containing the sequence of WT α-syn or K96/102R α-syn into SH-SY5Y cells and injecting an adenovirus containing the sequence of WT α-syn or K96/102R α-syn into the mouse striatum. Levels of the ubiquitin-proteasome system (UPS)-related makers ubiquitin (Ub) and UbE1, as well as the autophagy-lysosome pathway (ALP)-related markers LC3, P62 and lysosomal associated membrane protein 2A (LAMP2A), were also measured in SH-SY5Y cells transfected with lentivirus and mice injected with adenovirus. The results showed that METH exposure decreases the SUMOylation level of α-syn, although the expression of α-syn and SUMO-1 are increased. One possible cause is the reduction of UBC9 level. The increase in α-syn SUMOylation by UBC9 overexpression relieves METH-induced α-syn overexpression and aggregation, whereas the decrease in α-syn SUMOylation by SUMO-1 silencing exacerbates the same pathology. Furthermore, mutations in the major SUMOylation acceptor sites of α-syn also aggravate α-syn overexpression and aggregation by impairing degradation through the UPS and the ALP in vitro and in vivo. These results suggest that SUMOylation of α-syn plays a fundamental part in α-syn overexpression and aggregation induced by METH and could be a suitable target for the treatment of neurodegenerative diseases.https://www.frontiersin.org/article/10.3389/fncel.2018.00262/fullmethamphetamineSUMOylationalpha-synucleinaggregationdegradation |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Lin-nan Zhu Hong-hua Qiao Ling Chen Le-ping Sun Jia-liang Hui Yong-ling Lian Wei-bing Xie Jiu-yang Ding Jiu-yang Ding Yun-le Meng Bo-feng Zhu Ping-ming Qiu |
spellingShingle |
Lin-nan Zhu Hong-hua Qiao Ling Chen Le-ping Sun Jia-liang Hui Yong-ling Lian Wei-bing Xie Jiu-yang Ding Jiu-yang Ding Yun-le Meng Bo-feng Zhu Ping-ming Qiu SUMOylation of Alpha-Synuclein Influences on Alpha-Synuclein Aggregation Induced by Methamphetamine Frontiers in Cellular Neuroscience methamphetamine SUMOylation alpha-synuclein aggregation degradation |
author_facet |
Lin-nan Zhu Hong-hua Qiao Ling Chen Le-ping Sun Jia-liang Hui Yong-ling Lian Wei-bing Xie Jiu-yang Ding Jiu-yang Ding Yun-le Meng Bo-feng Zhu Ping-ming Qiu |
author_sort |
Lin-nan Zhu |
title |
SUMOylation of Alpha-Synuclein Influences on Alpha-Synuclein Aggregation Induced by Methamphetamine |
title_short |
SUMOylation of Alpha-Synuclein Influences on Alpha-Synuclein Aggregation Induced by Methamphetamine |
title_full |
SUMOylation of Alpha-Synuclein Influences on Alpha-Synuclein Aggregation Induced by Methamphetamine |
title_fullStr |
SUMOylation of Alpha-Synuclein Influences on Alpha-Synuclein Aggregation Induced by Methamphetamine |
title_full_unstemmed |
SUMOylation of Alpha-Synuclein Influences on Alpha-Synuclein Aggregation Induced by Methamphetamine |
title_sort |
sumoylation of alpha-synuclein influences on alpha-synuclein aggregation induced by methamphetamine |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Cellular Neuroscience |
issn |
1662-5102 |
publishDate |
2018-08-01 |
description |
Methamphetamine (METH) is an illegal and widely abused psychoactive stimulant. METH abusers are at high risk of neurodegenerative disorders, including Parkinson’s disease (PD). Previous studies have demonstrated that METH causes alpha-synuclein (α-syn) aggregation in the both laboratory animal and human. In this study, exposure to high METH doses increased the expression of α-syn and the small ubiquitin-related modifier 1 (SUMO-1). Therefore, we hypothesized that SUMOylation of α-syn is involved in high-dose METH-induced α-syn aggregation. We measured the levels of α-syn SUMOylation and these enzymes involved in the SUMOylation cycle in SH-SY5Y human neuroblastoma cells (SH-SY5Y cells), in cultures of C57 BL/6 primary mouse neurons and in brain tissues of mice exposure to METH. We also demonstrated the effect of α-syn SUMOylation on α-syn aggregation after METH exposure by overexpressing the key enzyme of the SUMOylation cycle or silencing SUMO-1 expression in vitro. Then, we make introduced mutations in the major SUMOylation acceptor sites of α-syn by transfecting a lentivirus containing the sequence of WT α-syn or K96/102R α-syn into SH-SY5Y cells and injecting an adenovirus containing the sequence of WT α-syn or K96/102R α-syn into the mouse striatum. Levels of the ubiquitin-proteasome system (UPS)-related makers ubiquitin (Ub) and UbE1, as well as the autophagy-lysosome pathway (ALP)-related markers LC3, P62 and lysosomal associated membrane protein 2A (LAMP2A), were also measured in SH-SY5Y cells transfected with lentivirus and mice injected with adenovirus. The results showed that METH exposure decreases the SUMOylation level of α-syn, although the expression of α-syn and SUMO-1 are increased. One possible cause is the reduction of UBC9 level. The increase in α-syn SUMOylation by UBC9 overexpression relieves METH-induced α-syn overexpression and aggregation, whereas the decrease in α-syn SUMOylation by SUMO-1 silencing exacerbates the same pathology. Furthermore, mutations in the major SUMOylation acceptor sites of α-syn also aggravate α-syn overexpression and aggregation by impairing degradation through the UPS and the ALP in vitro and in vivo. These results suggest that SUMOylation of α-syn plays a fundamental part in α-syn overexpression and aggregation induced by METH and could be a suitable target for the treatment of neurodegenerative diseases. |
topic |
methamphetamine SUMOylation alpha-synuclein aggregation degradation |
url |
https://www.frontiersin.org/article/10.3389/fncel.2018.00262/full |
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