Epigenetic upregulation of alpha-synuclein in the rats exposed to methamphetamine

Jiang, Wenda; Li, Ji; Zhang, Zhuang; Wang, Hongxin; Wang, Zhejian

doi:10.1016/j.ejphar.2014.10.043

Cited by 35 publications

(25 citation statements)

References 39 publications

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“…Brain samples (prefrontal cortex and striatum tissues) were removed quickly, dissected on ice and stored at −80°C. We selected the prefrontal cortex and striatum because α-syn level was significantly increased in those two brain regions (Jiang et al, 2014; Wang and Witt, 2014; Flack et al, 2017). All animal procedures were performed according to the National Institutes of Health (NIH) Guide for the Care and Use of Laboratory Animals and were pre-approved in advance by the Institutional Animal Care and Use Committee at the Southern Medical University.…”

Section: Methodsmentioning

confidence: 99%

“…Furthermore, METH causes pathological changes similar to neurodegenerative diseases like Parkinson’s disease (PD; Garwood et al, 2006; Morrow et al, 2011). In both laboratory animals and humans, METH exposure increases the expression of alpha-synuclein (α-syn) in the striatum and prefrontal cortex (Jiang et al, 2014; Wang and Witt, 2014; Flack et al, 2017). α-Syn, a natively unfolded neuronal protein enriched in presynaptic terminals, has been involved in several neurodegenerative diseases, including PD and dementia with Lewy bodies (LBs).…”

Section: Introductionmentioning

confidence: 99%

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SUMOylation of Alpha-Synuclein Influences on Alpha-Synuclein Aggregation Induced by Methamphetamine

Zhu

Qiao

Chen

et al. 2018

Front. Cell. Neurosci.

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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.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

SUMOylation of Alpha-Synuclein Influences on Alpha-Synuclein Aggregation Induced by Methamphetamine

Zhu

Qiao

Chen

et al. 2018

Front. Cell. Neurosci.

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“…Only a handful of studies employed neurotoxic doses of acute or chronic METH and found that self-administration of high-dose METH triggered changes in histone modifications and the expression of genes coding for proteins involved in chromatin remodeling 26 27 , whereas neurotoxic binge METH decreased the expression of several histone deacetylases (HDACs) 28 in the striatum. In the substantia nigra, high-dose METH injected over four days decreased DNA methylation within the promoter region of alpha-synuclein 29 .…”

mentioning

confidence: 95%

Neurotoxic Methamphetamine Doses Increase LINE-1 Expression in the Neurogenic Zones of the Adult Rat Brain

Moszczynska

Flack

Qiu

et al. 2015

Sci Rep

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Methamphetamine (METH) is a widely abused psychostimulant with the potential to cause neurotoxicity in the striatum and hippocampus. Several epigenetic changes have been described after administration of METH; however, there are no data regarding the effects of METH on the activity of transposable elements in the adult brain. The present study demonstrates that systemic administration of neurotoxic METH doses increases the activity of Long INterspersed Element (LINE-1) in two neurogenic niches in the adult rat brain in a promoter hypomethylation-independent manner. Our study also demonstrates that neurotoxic METH triggers persistent decreases in LINE-1 expression and increases the LINE-1 levels within genomic DNA in the striatum and dentate gyrus of the hippocampus, and that METH triggers LINE-1 retrotransposition in vitro. We also present indirect evidence for the involvement of glutamate (GLU) in LINE-1 activation. The results suggest that LINE-1 activation might occur in neurogenic areas in human METH users and might contribute to METH abuse-induced hippocampus-dependent memory deficits and impaired performance on several cognitive tasks mediated by the striatum.

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“…In the hereditary form of PD, genes encoding for parkin and α‐synuclein are mutated (Lesage & Brice, ), and in idiopathic PD, both proteins are aggregated in the brain (Baba et al ., ; Shimura et al ., ; Recasens & Dehay, ). High doses of METH non‐contingently administered in binge (four injections of 8–10 mg/kg every 2 h) or chronic protocols (20–24 mg/kg/day for 5–14 days) increase striatal and/or nigral levels of α‐synuclein (Yamamoto & Yang, ; Butler et al ., ; Jiang et al ., ; Gemechu et al ., ), as also seen with PD (Recasens & Dehay, ) and decrease parkin levels in the striatum (Moszczynska & Yamamoto, ). Overexpression of parkin attenuates damage to the nigrostriatal DA system in animal models of PD and in METH‐induced neurotoxicity, indicating that the deficits in parkin may be involved in pathologies of these conditions (LoBianco et al ., ; Liu et al ., ).…”

Section: Introductionmentioning

confidence: 96%

Self‐administration of methamphetamine alters gut biomarkers of toxicity

Flack

Persons

Kousik

et al. 2017

Eur J of Neuroscience

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Methamphetamine (METH) is a highly abused psychostimulant that is associated with an increased risk for developing Parkinson’s disease (PD). This enhanced vulnerability likely relates to the toxic effects of METH that overlap with PD pathology, for example, aberrant functioning of α-synuclein and parkin. In PD, peripheral factors are thought to contribute to central nervous system (CNS) degeneration. For example, α-synuclein levels in the enteric nervous system (ENS) are elevated, and this precedes the onset of motor symptoms. It remains unclear whether neurons of the ENS, particularly catecholaminergic neurons, exhibit signs of METH-induced toxicity as seen in the CNS. The aim of this study was to determine whether self-administered METH altered the levels of α-synuclein, parkin, tyrosine hydroxylase (TH), and dopamine-β-hydroxylase (DβH) in the myenteric plexus of the distal colon ENS. Young adult male Sprague-Dawley rats self-administered METH for 3 h per day for 14 days and controls were saline-yoked. Distal colon tissue was collected at 1, 14, or 56 days after the last operant session. Levels of α-synuclein were increased, while levels of parkin, TH, and DβH were decreased in the myenteric plexus in the METH-exposed rats at 1 day following the last operant session and returned to the control levels after 14 or 56 days of forced abstinence. The changes were not confined to neurofilament-positive neurons. These results suggest that colon biomarkers may provide early indications of METH-induced neurotoxicity, particularly in young chronic METH users who may be more susceptible to progression to PD later in life.

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Epigenetic upregulation of alpha-synuclein in the rats exposed to methamphetamine

Cited by 35 publications

References 39 publications

SUMOylation of Alpha-Synuclein Influences on Alpha-Synuclein Aggregation Induced by Methamphetamine

SUMOylation of Alpha-Synuclein Influences on Alpha-Synuclein Aggregation Induced by Methamphetamine

Neurotoxic Methamphetamine Doses Increase LINE-1 Expression in the Neurogenic Zones of the Adult Rat Brain

Self‐administration of methamphetamine alters gut biomarkers of toxicity

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