Inhibition of copper transporter 1 prevents α-synuclein pathology and alleviates nigrostriatal degeneration in AAV-based mouse model of Parkinson's disease

Gou, De Hai; Huang, Ting; Li, Wen; Gào, Xin; Haikal, Caroline; Wang, Xin He; Song, Dong Yan; Liang, Xin; Zhu, Lin; Tang, Yong; Ding, Chen; Li, Jia Yi

doi:10.1016/j.redox.2020.101795

Cited by 23 publications

(13 citation statements)

References 97 publications

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“…The main role of copper is mediated by its ability to trigger, maintain and even enhance free radical production. In general copper binding to α- Frontiers in Genetics frontiersin.org synuclein triggers increased proteogenic fibrillation and oxidative stress (Gou et al, 2021). However, under the influence of copper cyanobactin (Prohaska, 2011), the reduction of copper may be associated with iron accumulation, while iron deposition and consequent ferroptosis may be an important mechanism of dopaminergic neuronal death in PD (Wang et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

Machine learning-based characterization of cuprotosis-related biomarkers and immune infiltration in Parkinson’s disease

Zhao

Zhang

et al. 2022

Front. Genet.

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Background: Parkinson’s disease (PD) is a neurodegenerative disease commonly seen in the elderly. On the other hand, cuprotosis is a new copper-dependent type of cell death that can be observed in various diseases.Methods: This study aimed to identify potential novel biomarkers of Parkinson’s disease by biomarker analysis and to explore immune cell infiltration during the onset of cuprotosis. Gene expression profiles were retrieved from the GEO database for the GSE8397, GSE7621, GSE20163, and GSE20186 datasets. Three machine learning algorithms: the least absolute shrinkage and selection operator (LASSO), random forest, and support vector machine-recursive feature elimination (SVM-RFE) were used to screen for signature genes for Parkinson’s disease onset and cuprotosis-related genes (CRG). Immune cell infiltration was estimated by ssGSEA, and cuprotosis-related genes associated with immune cells and immune function were examined using spearman correlation analysis. Nomogram was created to validate the accuracy of these cuprotosis-related genes in predicting PD disease progression. Classification of Parkinson’s specimens using consensus clustering methods.Result: Three PD datasets from the Gene Expression Omnibus (GEO) database were combined after eliminating batch effects. By ssGSEA, we identified three cuprotosis-related genes ATP7A, SLC31A1, and DBT associated with immune cells or immune function in PD and more accurate for the diagnosis of Parkinson’s disease course. Patients could benefit clinically from a characteristic line graph based on these genes. Consistent clustering analysis identified two subtypes, with the C2 subtype exhibiting higher immune cell infiltration and immune function.Conclusion: In conclusion, our study reveals that several newly identified cuprotosis-related genes intervene in the progression of Parkinson’s disease through immune cell infiltration.

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Section: Discussionmentioning

confidence: 99%

Machine learning-based characterization of cuprotosis-related biomarkers and immune infiltration in Parkinson’s disease

Zhao

Zhang

et al. 2022

Front. Genet.

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“…The amount of copper released into the synapse, diffused extra-synaptically and taken up by astroglial copper transporters determines the strength of redox coupling which may vary from physiological to up- or down-regulated. The high extracellular level of copper elicits low surface expression of CTR1 [ 44 ], that may be mechanistically linked to Parkinson’s and Alzheimer’s disease mechanisms [ 97 , 98 ] or schizophrenia [ 99 ]. Metabolic profiling of brains [ 100 , 101 , 102 ] and serum [ 103 ] of AD subjects suggests a possible role for altered spermidine metabolism correlating AD indicators.…”

Section: Discussionmentioning

confidence: 99%

Dual Role for Astroglial Copper-Assisted Polyamine Metabolism during Intense Network Activity

et al. 2021

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Astrocytes serve essential roles in human brain function and diseases. Growing evidence indicates that astrocytes are central players of the feedback modulation of excitatory Glu signalling during epileptiform activity via Glu-GABA exchange. The underlying mechanism results in the increase of tonic inhibition by reverse operation of the astroglial GABA transporter, induced by Glu-Na+ symport. GABA, released from astrocytes, is synthesized from the polyamine (PA) putrescine and this process involves copper amino oxidase. Through this pathway, putrescine can be considered as an important source of inhibitory signaling that counterbalances epileptic discharges. Putrescine, however, is also a precursor for spermine that is known to enhance gap junction channel communication and, consequently, supports long-range Ca2+ signaling and contributes to spreading of excitatory activity through the astrocytic syncytium. Recently, we presented the possibility of neuron-glia redox coupling through copper (Cu+/Cu2+) signaling and oxidative putrescine catabolism. In the current work, we explore whether the Cu+/Cu2+ homeostasis is involved in astrocytic control on neuronal excitability by regulating PA catabolism. We provide supporting experimental data underlying this hypothesis. We show that the blockade of copper transporter (CTR1) by AgNO3 (3.6 µM) prevents GABA transporter-mediated tonic inhibitory currents, indicating causal relationship between copper (Cu+/Cu2+) uptake and the catabolism of putrescine to GABA in astrocytes. In addition, we show that MnCl2 (20 μM), an inhibitor of the divalent metal transporter DMT1, also prevents the astrocytic Glu-GABA exchange. Furthermore, we observed that facilitation of copper uptake by added CuCl2 (2 µM) boosts tonic inhibitory currents. These findings corroborate the hypothesis that modulation of neuron-glia coupling by copper uptake drives putrescine → GABA transformation, which leads to subsequent Glu-GABA exchange and tonic inhibition. Findings may in turn highlight the potential role of copper signaling in fine-tuning the activity of the tripartite synapse.

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“…Pole test was used to assess the motor coordination and balance of mice, and open field test (OFT) was used to assess the spontaneous activity of mice, as previously described [ 37 , 38 ]. In the pole test, a steel pipe with length of 55 cm and diameter of 1 cm was tightly wrapped in white antiskid gauze and fixed on plastic foam base.…”

Section: Methodsmentioning

confidence: 99%

Long-term hyperglycemia aggravates α-synuclein aggregation and dopaminergic neuronal loss in a Parkinson’s disease mouse model

Yuan

Sun

et al. 2022

Transl Neurodegener

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Background Growing evidence suggests an association between Parkinson’s disease (PD) and diabetes mellitus (DM). At the cellular level, long-term elevated levels of glucose have been shown to lead to nigrostriatal degeneration in PD models. However, the underlying mechanism is still unclear. Previously, we have elucidated the potential of type 2 diabetes mellitus (T2DM) in facilitating PD progression, involving aggregation of both alpha-synuclein (α-syn) and islet amyloid polypeptide in the pancreatic and brain tissues. However, due to the complicated effect of insulin resistance on PD onset, the actual mechanism of hyperglycemia-induced dopaminergic degeneration remains unknown. Methods We employed the type 1 diabetes mellitus (T1DM) model induced by streptozotocin (STZ) injection in a transgenic mouse line (BAC-α-syn-GFP) overexpressing human α-syn, to investigate the direct effect of elevated blood glucose on nigrostriatal degeneration. Results STZ treatment induced more severe pathological alterations in the pancreatic islets and T1DM symptoms in α-syn-overexpressing mice than in wild-type mice, at one month and three months after STZ injections. Behavioral tests evaluating motor performance confirmed the nigrostriatal degeneration. Furthermore, there was a marked decrease in dopaminergic profiles and an increase of α-syn accumulation and Serine 129 (S129) phosphorylation in STZ-treated α-syn mice compared with the vehicle-treated mice. In addition, more severe neuroinflammation was observed in the brains of the STZ-treated α-syn mice. Conclusion Our results solidify the potential link between DM and PD, providing insights into how hyperglycemia induces nigrostriatal degeneration and contributes to pathogenic mechanisms in PD.

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Inhibition of copper transporter 1 prevents α-synuclein pathology and alleviates nigrostriatal degeneration in AAV-based mouse model of Parkinson's disease

Cited by 23 publications

References 97 publications

Machine learning-based characterization of cuprotosis-related biomarkers and immune infiltration in Parkinson’s disease

Machine learning-based characterization of cuprotosis-related biomarkers and immune infiltration in Parkinson’s disease

Dual Role for Astroglial Copper-Assisted Polyamine Metabolism during Intense Network Activity

Long-term hyperglycemia aggravates α-synuclein aggregation and dopaminergic neuronal loss in a Parkinson’s disease mouse model

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