Transfer of α-synuclein from neurons to oligodendrocytes triggers myelin sheath destruction in methamphetamine administration mice

Ding, Jiuyang; Huang, Jian; Xia, Bing; Hu, Shanshan; Fan, Haoliang; Dai, Jialin; Zhu, Ling; Wang, Jiawen; Le, Cuiyun; Qiu, Pingming; Wang, Yuanhe

doi:10.1016/j.toxlet.2021.09.005

Cited by 10 publications

(4 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Both animal and human studies have shown that VGB could induce intramyelinic edema, 15 , 45 – 48 and studies showed the injury of myelin was associated with autophagy. 49 , 50 Thus, we presume rapamycin could induce autophagy via partial mTOR inhibition to prevent the occurrence of VABAM. Paradoxically, the TSC patients with mTOR hyperactivation should have a higher incidence of VABAM based on that assumption, but this is not the case.…”

Section: Discussionmentioning

confidence: 97%

Vigabatrin-associated brain abnormalities on MRI in tuberous sclerosis complex patients with infantile spasms: are they preventable?

Wan

Wang

et al. 2022

Ther Adv Neurol Disord

View full text Add to dashboard Cite

Background: Vigabatrin (VGB) is currently the most widely prescribed first-line medication for individuals with infantile spasms (IS) and especially for those with tuberous sclerosis complex (TSC), with demonstrated efficacy. Meanwhile, its adverse events, such as vigabatrin-associated brain abnormalities on magnetic resonance imaging (MRI; VABAM), have also been widely reported. Objectives: The objectives of this study were to observe the occurrences of VABAM in patients with IS caused by TSC (IST) and further explore the associated risk factors. Methods: Children with IS receiving VGB were recruited from our institution; clinical, imaging, and medication data were collected. Cerebral MRI was reviewed to determine the occurrence of VABAM. Group comparisons (IS caused by TSC and other etiologies) were performed; subgroup analyses on IST were also performed. Next, a retrospective cohort study of children taking VGB was conducted to explore risk/protective factors associated with VABAM. Results: The study enrolled 172 children with IS who received VGB. VABAM was observed in 38 patients (22.1%) with a peak dosage of 103.5 ± 26.7 mg/kg/day. Subsequent analysis found the incidence of VABAM was significantly lower in the 80 patients with IST than in the 92 patients with IS caused by other etiologies (10% versus 32.6%, p-value < 0.001). In subgroup analyses within the IST cohort, VABAM was significantly lower in children who received concomitant rapamycin therapy. Univariate and multivariate logistic regression analysis of the 172 IS children showed that treatment with rapamycin was the independent factor associated with a lower risk of VABAM; similar results were observed in the survival analysis. Conclusion: The incidence of VABAM was significantly lower in IST patients. Further research is needed to examine the mechanisms that underlie this phenomenon and to determine if treatment with rapamycin may reduce the risk of VABAM.

show abstract

Section: Discussionmentioning

confidence: 97%

Vigabatrin-associated brain abnormalities on MRI in tuberous sclerosis complex patients with infantile spasms: are they preventable?

Wan

Wang

et al. 2022

Ther Adv Neurol Disord

View full text Add to dashboard Cite

show abstract

“…It is likely that, in those cells where mTOR is upregulated and autophagy is suppressed, the eventual accumulation of α-syn triggers a biochemical cascade that affects gene expression [65,73], cell proliferation [71], and cell differentiation [74]. This shifts the original question of investigating whether α-syn is highly expressed in GBM to the following question: does α-syn take an active role in the neurobiology of GBM?…”

Section: Discussionmentioning

confidence: 99%

Occurrence of Total and Proteinase K-Resistant Alpha-Synuclein in Glioblastoma Cells Depends on mTOR Activity

Ryskalin

Ferese

Morucci

et al. 2022

Cancers

View full text Add to dashboard Cite

Alpha-synuclein (α-syn) is a protein considered to be detrimental in a number of degenerative disorders (synucleinopathies) of which α-syn aggregates are considered a pathological hallmark. The clearance of α-syn strongly depends on autophagy, which can be stimulated by inhibiting the mechanistic target of rapamycin (mTOR). Thus, the overexpression of mTOR and severe autophagy suppression may produce α-syn accumulation, including the proteinase K-resistant protein isoform. Glioblastoma multiforme (GBM) is a lethal brain tumor that features mTOR overexpression and severe autophagy inhibition. Cell pathology in GBM is reminiscent of a fast, progressive degenerative disorder. Therefore, the present work questions whether, as is analogous to neurons during degenerative disorders, an overexpression of α-syn occurs within GBM cells. A high amount of α-syn was documented in GBM cells via real-time PCR (RT-PCR), Western blotting, immunohistochemistry, immuno-fluorescence, and ultrastructural stoichiometry, compared with the amount of β- and γ-synucleins and compared with the amount of α-syn counted within astrocytes. The present study indicates that (i) α-syn is overexpressed in GBM cells, (ii) α-syn expression includes a proteinase-K resistant isoform, (iii) α-syn is dispersed from autophagy-like vacuoles to the cytosol, (iv) α-syn overexpression and cytosol dispersion are mitigated by rapamycin, and (v) the α-syn-related GBM-like phenotype is mitigated by silencing the SNCA gene.

show abstract

“…L2017208) and were performed according to ethical standards described in the NIH guidelines. The chronic METH-abuse mice model was established according to the 14-day administration schedule ( Table 1 ), which was determined based on our previous studies [ 8 , 27 , 28 ]. And 10 mg/kg or 30 mg/kg of ICS was administered orally to investigate the intervention effect of ICS on METH-induced neurotoxicity by referring to an earlier study [ 29 ].…”

Section: Methodsmentioning

confidence: 99%

Icariside II Attenuates Methamphetamine-Induced Neurotoxicity and Behavioral Impairments via Activating the Keap1-Nrf2 Pathway

Huang

Ding

Wang

et al. 2022

Oxidative Medicine and Cellular Longevity

Self Cite

View full text Add to dashboard Cite

Chronic and long-term methamphetamine (METH) abuse is bound to cause damages to multiple organs and systems, especially the central nervous system (CNS). Icariside II (ICS), a type of flavonoid and one of the main active ingredients of the traditional Chinese medicine Epimedium, exhibits a variety of biological and pharmacological properties such as anti-inflammatory, antioxidant, and anticancer activities. However, whether ICS could protect against METH-induced neurotoxicity remains unknown. Based on a chronic METH abuse mouse model, we detected the neurotoxicity after METH exposure and determined the intervention effect of ICS and the potential mechanism of action. Here, we found that METH could trigger neurotoxicity, which was characterized by loss of dopaminergic neurons, depletion of dopamine (DA), activation of glial cells, upregulation of α-synuclein (α-syn), abnormal dendritic spine plasticity, and dysfunction of motor coordination and balance. ICS treatment, however, alleviated the above-mentioned neurotoxicity elicited by METH. Our data also indicated that when ICS combated METH-induced neurotoxicity, it was accompanied by partial correction of the abnormal Kelch 2 like ECH2 associated protein 1 (Keap1)-nuclear factor erythroid-2-related factor 2 (Nrf2) pathway and oxidative stress response. In the presence of ML385, an inhibitor of Nrf2, ICS failed to activate the Nrf2-related protein expression and reduce the oxidative stress response. More importantly, ICS could not attenuate METH-induced dopaminergic neurotoxicity and behavioral damage when the Nrf2 was inhibited, suggesting that the neuroprotective effect of ICS on METH-induced neurotoxicity was dependent on activating the Keap1-Nrf2 pathway. Although further research is needed to dig deeper into the actual molecular targets of ICS, it is undeniable that the current results imply the potential value of ICS to reduce the neurotoxicity of METH abusers.

show abstract

Transfer of α-synuclein from neurons to oligodendrocytes triggers myelin sheath destruction in methamphetamine administration mice

Cited by 10 publications

References 38 publications

Vigabatrin-associated brain abnormalities on MRI in tuberous sclerosis complex patients with infantile spasms: are they preventable?

Vigabatrin-associated brain abnormalities on MRI in tuberous sclerosis complex patients with infantile spasms: are they preventable?

Occurrence of Total and Proteinase K-Resistant Alpha-Synuclein in Glioblastoma Cells Depends on mTOR Activity

Icariside II Attenuates Methamphetamine-Induced Neurotoxicity and Behavioral Impairments via Activating the Keap1-Nrf2 Pathway

Contact Info

Product

Resources

About