Abstract
Aggregation of α-synuclein (α-syn) and α-syn cytotoxicity are hallmarks of sporadic and familial Parkinson’s disease (PD). Nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-dependent enhancement of the expression of the 20S proteasome core particles (20S CPs) and regulatory particles (RPs) increases proteasome activity, which can promote α-syn clearance in PD. Activation of peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) may reduce oxidative stress by strongly inducing Nrf2 gene expression. In the present study, tetramethylpyrazine nitrone (TBN), a potent-free radical scavenger, promoted α-syn clearance by the ubiquitin–proteasome system (UPS) in cell models overexpressing the human A53T mutant α-syn. In the α-syn transgenic mice model, TBN improved motor impairment, decreased the products of oxidative damage, and down-regulated the α-syn level in the serum. TBN consistently up-regulated PGC-1α and Nrf2 expression in tested models of PD. Additionally, TBN similarly enhanced the proteasome 20S subunit beta 8 (Psmb8) expression, which is linked to chymotrypsin-like proteasome activity. Furthermore, TBN increased the mRNA levels of both the 11S RPs subunits Pa28αβ and a proteasome chaperone, known as the proteasome maturation protein (Pomp). Interestingly, specific siRNA targeting of Nrf2 blocked TBN’s effects on Psmb8, Pa28αβ, Pomp expression, and α-syn clearance. In conclusion, TBN promotes the clearance of α-syn via Nrf2-mediated UPS activation, and it may serve as a potentially disease-modifying therapeutic agent for PD.
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Data Availability
All inquiries regarding TBN should be directed to Yewei Sun or Zaijun Zhang. TBN will be made available through a material transfer agreement.
References
Abu Shelbayeh, O., Arroum, T., Morris, S., & Busch, K. B. (2023). PGC-1α is a master regulator of mitochondrial lifecycle and ROS stress response. Antioxidants (basel). https://doi.org/10.3390/antiox12051075
Akiyama, K., Yokota, K., Kagawa, S., Shimbara, N., Tamura, T., Akioka, H., Nothwang, H. G., Noda, C., Tanaka, K., & Ichihara, A. (1994). cDNA cloning and interferon gamma down-regulation of proteasomal subunits X and Y. Science, 265(5176), 1231–1234. https://doi.org/10.1126/science.8066462
Bao, X. Q., Kong, X. C., Qian, C., & Zhang, D. (2012). Flz protects dopaminergic neuron through activating protein kinase b/mammalian target of rapamycin pathway and inhibiting Rtp801 expression in Parkinson’s Disease Models. Neuroscience, 202, 396–404. https://doi.org/10.1016/j.neuroscience.2011.11.036
Baxter, P. S., Márkus, N. M., Dando, O., He, X., Al-Mubarak, B. R., Qiu, J., & Hardingham, G. E. (2021). Targeted de-repression of neuronal Nrf2 inhibits α-synuclein accumulation. Cell Death & Disease, 12(2), 218. https://doi.org/10.1038/s41419-021-03507-z
Beal, M. F. (2010). Parkinson’s disease: A model dilemma. Nature, 466(7310), S8-10. https://doi.org/10.1038/466S8a
Bi, W. F., Yang, H. Y., Liu, J. C., Cheng, T. H., Chen, C. H., Shih, C. M., Lin, H., Wang, T. C., Lian, W. S., Chen, J. J., Chiu, H. C., & Chang, N. C. (2005). Inhibition of cyclic strain-induced endothelin-1 secretion by tetramethylpyrazine. Clinical and Experimental Pharmacology and Physiology, 32(7), 536–540. https://doi.org/10.1111/j.1440-1681.2005.04227.x
Burbulla, L. F., Song, P., Mazzulli, J. R., Zampese, E., Wong, Y. C., Jeon, S., Santos, D. P., Blanz, J., Obermaier, C. D., Strojny, C., Savas, J. N., Kiskinis, E., Zhuang, X., Kruger, R., Surmeier, D. J., & Krainc, D. (2017). Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson’s disease. Science, 357(6357), 1255–1261. https://doi.org/10.1126/science.aam9080
Chen, P. C., Vargas, M. R., Pani, A. K., Smeyne, R. J., Johnson, D. A., Kan, Y. W., & Johnson, J. A. (2009). Nrf2-mediated neuroprotection in the MPTP mouse model of Parkinson’s disease: Critical role for the astrocyte. Proceedings of the National Academy of Sciences U S A, 106(8), 2933–2938. https://doi.org/10.1073/pnas.0813361106
Cheng, A., Wan, R., Yang, J. L., Kamimura, N., Son, T. G., Ouyang, X., Luo, Y., Okun, E., & Mattson, M. P. J. N. C. (2012). Involvement of PGC-1α in the formation and maintenance of neuronal dendritic spines. Nature Communications, 3(3), 1250. https://doi.org/10.1038/ncomms2238
Ciron, C., Zheng, L., Bobela, W., Knott, G. W., Leone, T. C., Kelly, D. P., & Schneider, B. L. (2015). PGC-1α activity in nigral dopamine neurons determines vulnerability to α-synuclein. Acta Neuropathologica Communications, 3, 16. https://doi.org/10.1186/s40478-015-0200-8
Dauer, W., & Przedborski, S. (2003). Parkinson’s disease: Mechanisms and models. Neuron, 39(6), 889–909. https://doi.org/10.1016/s0896-6273(03)00568-3
Dayalan Naidu, S., & Dinkova-Kostova, A. T. (2020). KEAP1, a cysteine-based sensor and a drug target for the prevention and treatment of chronic disease. Open Biology, 10(6), 200105. https://doi.org/10.1098/rsob.200105
Delaidelli, A., Richner, M., Jiang, L., van der Laan, A., Christiansen, B. J., & I., Ferreira, N., Nyengaard, J. R., Vægter, C. B., Jensen, P. H., Mackenzie, I. R., Sorensen, P. H., & Jan, A. (2021). α-Synuclein pathology in Parkinson disease activates homeostatic NRF2 anti-oxidant response. Acta Neuropathologica Communications, 9(1), 105. https://doi.org/10.1186/s40478-021-01209-3
Ding, H., Wang, X., Wang, H., Zhu, L., Wang, Q., Jia, Y., Wei, W., Zhou, C., Wu, H., & Ding, K. (2017). Nrf2-ARE signaling provides neuroprotection in traumatic brain injury via modulation of the ubiquitin proteasome system. Neurochemistry International, 111, 32–44. https://doi.org/10.1016/j.neuint.2017.04.016
Elkouzi, A., Vedam-Mai, V., Eisinger, R. S., & Okun, M. S. (2019). Emerging therapies in Parkinson disease—repurposed drugs and new approaches. Nature Reviews. Neurology, 15(4), 204–223. https://doi.org/10.1038/s41582-019-0155-7
Eschbach, J., von Einem, B., Müller, K., Bayer, H., Scheffold, A., Morrison, B. E., Rudolph, K. L., Thal, D. R., Witting, A., Weydt, P., Otto, M., Fauler, M., Liss, B., McLean, P. J., Spada, A. R., Ludolph, A. C., Weishaupt, J. H., & Danzer, K. M. (2015). Mutual exacerbation of peroxisome proliferator-activated receptor γ coactivator 1α deregulation and α-synuclein oligomerization. Annals of Neurology, 77(1), 15–32. https://doi.org/10.1002/ana.24294
Fields, C. R., Bengoa-Vergniory, N., & Wade-Martins, R. (2019). Targeting alpha-synuclein as a therapy for Parkinson’s disease. Frontiers in Molecular Neuroscience, 12, 299. https://doi.org/10.3389/fnmol.2019.00299
Fu, M. H., Wu, C. W., Lee, Y. C., Hung, C. Y., Chen, I. C., & Wu, K. L. H. (2018). Nrf2 activation attenuates the early suppression of mitochondrial respiration due to the α-synuclein overexpression. Biomedical Journal, 41(3), 169–183. https://doi.org/10.1016/j.bj.2018.02.005
Giasson, B. I., Duda, J. E., Quinn, S. M., Zhang, B., Trojanowski, J. Q., & Lee, V. M. (2002). Neuronal alpha-synucleinopathy with severe movement disorder in mice expressing A53T human alpha-synuclein. Neuron, 34(4), 521–533. https://doi.org/10.1016/s0896-6273(02)00682-7
Grosso Jasutkar, H., Oh, S. E., & Mouradian, M. M. (2022). Therapeutics in the pipeline targeting α-synuclein for Parkinson’s Disease. Pharmacological Reviews, 74(1), 207–237. https://doi.org/10.1124/pharmrev.120.000133
Guo, B., Zheng, C., Cao, J., Luo, F., Li, H., Hu, S., Mingyuan Lee, S., Yang, X., Zhang, G., Zhang, Z., Sun, Y., & Wang, Y. (2023). Tetramethylpyrazine nitrone exerts neuroprotection via activation of PGC-1α/Nrf2 pathway in Parkinson’s disease models. Journal of Advanced Research. https://doi.org/10.1016/j.jare.2023.11.021
Gureev, A. P., Shaforostova, E. A., & Popov, V. N. (2019). Regulation of mitochondrial biogenesis as a way for active longevity: interaction between the Nrf2 and PGC-1α signaling pathways. Frontiers in Genetics, 10, 435. https://doi.org/10.3389/fgene.2019.00435
He, X., & Ma, Q. (2009). NRF2 cysteine residues are critical for oxidant/electrophile-sensing, Kelch-like ECH-associated protein-1-dependent ubiquitination-proteasomal degradation, and transcription activation. Molecular Pharmacology, 76(6), 1265–1278. https://doi.org/10.1124/mol.109.058453
Jang, J., Wang, Y., Kim, H. S., Lalli, M. A., & Kosik, K. S. (2014). Nrf2, a regulator of the proteasome, controls self-renewal and pluripotency in human embryonic stem cells. Stem Cells, 32(10), 2616–2625. https://doi.org/10.1002/stem.1764
Jankovic, J., & Tan, E. K. (2020). Parkinson’s disease: Etiopathogenesis and treatment. Journal of Neurology, Neurosurgery and Psychiatry, 91(8), 795–808. https://doi.org/10.1136/jnnp-2019-322338
Kumar, V., Singh, D., Singh, B. K., Singh, S., Mittra, N., Jha, R. R., Patel, D. K., & Singh, C. (2018). Alpha-synuclein aggregation, Ubiquitin proteasome system impairment, and L-Dopa response in zinc-induced Parkinsonism: Resemblance to sporadic Parkinson’s disease. Molecular and Cellular Biochemistry, 444(1–2), 149–160. https://doi.org/10.1007/s11010-017-3239-y
Lastres-Becker, I., Garcia-Yague, A. J., Scannevin, R. H., Casarejos, M. J., Kugler, S., Rabano, A., & Cuadrado, A. (2016). Repurposing the NRF2 activator dimethyl fumarate as therapy against synucleinopathy in Parkinson’s disease. Antioxidants & Redox Signaling, 25(2), 61–77. https://doi.org/10.1089/ars.2015.6549
Lastres-Becker, I., Ulusoy, A., Innamorato, N. G., Sahin, G., Rabano, A., Kirik, D., & Cuadrado, A. (2012). alpha-Synuclein expression and Nrf2 deficiency cooperate to aggravate protein aggregation, neuronal death and inflammation in early-stage Parkinson’s disease. Human Molecular Genetics, 21(14), 3173–3192. https://doi.org/10.1093/hmg/dds143
Lees, K. R., Zivin, J. A., Ashwood, T., Davalos, A., Davis, S. M., Diener, H. C., Grotta, J., Lyden, P., Shuaib, A., Hardemark, H. G., & Wasiewski, W. W. (2006). NXY-059 for acute ischemic stroke. New England Journal of Medicine, 354(6), 588–600. https://doi.org/10.1056/NEJMoa052980
Lu, C., Zhang, J., Shi, X., Miao, S., Bi, L., Zhang, S., Yang, Q., Zhou, X., Zhang, M., Xie, Y., Miao, Q., & Wang, S. (2014). Neuroprotective effects of tetramethylpyrazine against dopaminergic neuron injury in a rat model of Parkinson’s disease induced by MPTP. International Journal of Biological Sciences, 10(4), 350–357. https://doi.org/10.7150/ijbs.8366
Luo, X., Yu, Y., Xiang, Z., Wu, H., Ramakrishna, S., Wang, Y., So, K. F., Zhang, Z., & Xu, Y. (2017). Tetramethylpyrazine nitrone protects retinal ganglion cells against N-methyl-d-aspartate-induced excitotoxicity. Journal of Neurochemistry, 141(3), 373–386. https://doi.org/10.1111/jnc.13970
Maples, K. R., Green, A. R., & Floyd, R. A. (2004). Nitrone-related therapeutics: Potential of NXY-059 for the treatment of acute ischaemic stroke. CNS Drugs, 18(15), 1071–1084. https://doi.org/10.2165/00023210-200418150-00003
Mehra, S., Sahay, S., & Maji, S. K. (2019). α-Synuclein misfolding and aggregation: Implications in Parkinson’s disease pathogenesis. Biochim Biophys Acta Proteins Proteom, 1867(10), 890–908. https://doi.org/10.1016/j.bbapap.2019.03.001
Ngo, V., & Duennwald, M. L. (2022). Nrf2 and oxidative stress: A general overview of mechanisms and implications in human disease. Antioxidants (basel). https://doi.org/10.3390/antiox11122345
Ngo, V., Karunatilleke, N. C., Brickenden, A., Choy, W. Y., & Duennwald, M. L. (2022). Oxidative stress-induced misfolding and inclusion formation of Nrf2 and Keap1. Antioxidants (basel). https://doi.org/10.3390/antiox11020243
Olanow, C. W., & Kordower, J. H. (2017). Targeting α-Synuclein as a therapy for Parkinson’s disease: The battle begins. Movement Disorders, 32(2), 203–207. https://doi.org/10.1002/mds.26935
Pajares, M., Cuadrado, A., & Rojo, A. I. (2017). Modulation of proteostasis by transcription factor NRF2 and impact in neurodegenerative diseases. Redox Biology, 11, 543–553. https://doi.org/10.1016/j.redox.2017.01.006
Paxinou, E., Chen, Q., Weisse, M., Giasson, B. I., Norris, E. H., Rueter, S. M., Trojanowski, J. Q., Lee, V. M., & Ischiropoulos, H. (2001). Induction of alpha-synuclein aggregation by intracellular nitrative insult. The Journal of NeurosciEnce, 21(20), 8053–8061. https://doi.org/10.1523/JNEUROSCI.21-20-08053.2001
Pickering, A. M., Linder, R. A., Zhang, H., Forman, H. J., & Davies, K. J. A. (2012). Nrf2-dependent induction of proteasome and Pa28αβ regulator are required for adaptation to oxidative stress. Journal of Biological Chemistry, 287(13), 10021–10031. https://doi.org/10.1074/jbc.M111.277145
Selkoe, D. J. (2019). Alzheimer disease and aducanumab: Adjusting our approach. Nature Reviews Neurology, 15(7), 365–366. https://doi.org/10.1038/s41582-019-0205-1
Siddiqui, A., Chinta, S. J., Mallajosyula, J. K., Rajagopolan, S., Hanson, I., Rane, A., Melov, S., & Andersen, J. K. (2012). Selective binding of nuclear alpha-synuclein to the PGC1alpha promoter under conditions of oxidative stress may contribute to losses in mitochondrial function: Implications for Parkinson’s disease. Free Radical Biology & Medicine, 53(4), 993–1003. https://doi.org/10.1016/j.freeradbiomed.2012.05.024
Simon, D. K., Tanner, C. M., & Brundin, P. (2020). Parkinson disease epidemiology, pathology, genetics, and pathophysiology. Clinics in Geriatric Medicine, 36(1), 1–12. https://doi.org/10.1016/j.cger.2019.08.002
Skibinski, G., Hwang, V., Ando, D. M., Daub, A., Lee, A. K., Ravisankar, A., Modan, S., Finucane, M. M., Shaby, B. A., & Finkbeiner, S. (2017). Nrf2 mitigates LRRK2- and alpha-synuclein-induced neurodegeneration by modulating proteostasis. Proceedings of the National Academy of Sciences U S A, 114(5), 1165–1170. https://doi.org/10.1073/pnas.1522872114
Soyal, S. M., Zara, G., Ferger, B., Felder, T. K., Kwik, M., Nofziger, C., Dossena, S., Schwienbacher, C., Hicks, A. A., Pramstaller, P. P., Paulmichl, M., Weis, S., & Patsch, W. (2019). The PPARGC1A locus and CNS-specific PGC-1α isoforms are associated with Parkinson’s Disease. Neurobiology of Diseases, 121, 34–46. https://doi.org/10.1016/j.nbd.2018.09.016
Stoker, T. B., & Barker, R. A. (2020). Recent developments in the treatment of Parkinson’s Disease. F1000Res, 9, 862.
St-Pierre, J., Drori, S., Uldry, M., Silvaggi, J. M., Rhee, J., Jager, S., Handschin, C., Zheng, K., Lin, J., Yang, W., Simon, D. K., Bachoo, R., & Spiegelman, B. M. (2006). Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell, 127(2), 397–408. https://doi.org/10.1016/j.cell.2006.09.024
Sun, Y., Jiang, J., Zhang, Z., Yu, P., Wang, L., Xu, C., Liu, W., & Wang, Y. (2008). Antioxidative and thrombolytic TMP nitrone for treatment of ischemic stroke. Bioorganic & Medicinal Chemistry, 16(19), 8868–8874. https://doi.org/10.1016/j.bmc.2008.08.075
Ugun-Klusek, A., Tatham, M. H., Elkharaz, J., Constantin-Teodosiu, D., Lawler, K., Mohamed, H., Paine, S. M., Anderson, G., John Mayer, R., Lowe, J., Ellen Billett, E., & Bedford, L. (2017). Continued 26S proteasome dysfunction in mouse brain cortical neurons impairs autophagy and the Keap1-Nrf2 oxidative defence pathway. Cell Death & Disease, 8(1), e2531. https://doi.org/10.1038/cddis.2016.443
Visanji, N. P., Brotchie, J. M., Kalia, L. V., Koprich, J. B., Tandon, A., Watts, J. C., & Lang, A. E. (2016). α-synuclein-based animal models of Parkinson’s Disease: Challenges and opportunities in a New Era. Trends in Neurosciences, 39(11), 750–762. https://doi.org/10.1016/j.tins.2016.09.003
Webb, J. L., Ravikumar, B., Atkins, J., Skepper, J. N., & Rubinsztein, D. C. (2003). Alpha-Synuclein is degraded by both autophagy and the proteasome. Journal of Biological Chemistry, 278(27), 25009–25013. https://doi.org/10.1074/jbc.M300227200
Xu, D., Duan, H., Zhang, Z., Cui, W., Wang, L., Sun, Y., Lang, M., Hoi, P. M., Han, Y., Wang, Y., & Lee, S. M. (2014a). The novel tetramethylpyrazine bis-nitrone (TN-2) protects against MPTP/MPP+-induced neurotoxicity via inhibition of mitochondrial-dependent apoptosis. Journal of Neuroimmune Pharmacology, 9(2), 245–258. https://doi.org/10.1007/s11481-013-9514-0
Xu, D. P., Zhang, K., Zhang, Z. J., Sun, Y. W., Guo, B. J., Wang, Y. Q., Hoi, P. M., Han, Y. F., & Lee, S. M. (2014b). A novel tetramethylpyrazine bis-nitrone (TN-2) protects against 6-hydroxyldopamine-induced neurotoxicity via modulation of the NF-kappaB and the PKCalpha/PI3-K/Akt pathways. Neurochemistry International, 78, 76–85. https://doi.org/10.1016/j.neuint.2014.09.001
Zhang, G., Zhang, F., Zhang, T., Gu, J., Li, C., Sun, Y., Yu, P., Zhang, Z., & Wang, Y. (2016a). Tetramethylpyrazine nitrone improves neurobehavioral functions and confers neuroprotection on rats with traumatic brain injury. Neurochemical Research, 41(11), 2948–2957. https://doi.org/10.1007/s11064-016-2013-y
Zhang, G., Zhang, T., Li, N., Wu, L., Gu, J., Li, C., Zhao, C., Liu, W., Shan, L., Yu, P., Yang, X., Tang, Y., Yang, G. Y., Wang, Y., Sun, Y., & Zhang, Z. (2018a). Tetramethylpyrazine nitrone activates the BDNF/Akt/CREB pathway to promote post-ischaemic neuroregeneration and recovery of neurological functions in rats. British Journal of Pharmacology, 175(3), 517–531. https://doi.org/10.1111/bph.14102
Zhang, G., Zhang, T., Wu, L., Zhou, X., Gu, J., Li, C., Liu, W., Long, C., Yang, X., Shan, L., Xu, L., Wang, Y., Sun, Y., & Zhang, Z. (2018b). Neuroprotective effect and mechanism of action of tetramethylpyrazine nitrone for ischemic stroke therapy. Neuromolecular Medicine, 20(1), 97–111. https://doi.org/10.1007/s12017-018-8478-x
Zhang, T., Gu, J., Wu, L., Li, N., Sun, Y., Yu, P., Wang, Y., Zhang, G., & Zhang, Z. (2017). Neuroprotective and axonal outgrowth-promoting effects of tetramethylpyrazine nitrone in chronic cerebral hypoperfusion rats and primary hippocampal neurons exposed to hypoxia. Neuropharmacology, 118, 137–147. https://doi.org/10.1016/j.neuropharm.2017.03.022
Zhang, Z., Zhang, G., Sun, Y., Szeto, S. S., Law, H. C., Quan, Q., Li, G., Yu, P., Sho, E., Siu, M. K., Lee, S. M., Chu, I. K., & Wang, Y. (2016b). Tetramethylpyrazine nitrone, a multifunctional neuroprotective agent for ischemic stroke therapy. Science and Reports, 6, 37148. https://doi.org/10.1038/srep37148
Zhao, H., Xu, M. L., Zhang, Q., Guo, Z. H., Peng, Y., Qu, Z. Y., & Li, Y. N. (2014). Tetramethylpyrazine alleviated cytokine synthesis and dopamine deficit and improved motor dysfunction in the mice model of Parkinson’s disease. Neurological Sciences, 35(12), 1963–1967. https://doi.org/10.1007/s10072-014-1871-9
Zheng, B., Liao, Z., Locascio, J. J., Lesniak, K. A., Roderick, S. S., Watt, M. L., Eklund, A. C., Zhang-James, Y., Kim, P. D., Hauser, M. A., Grunblatt, E., Moran, L. B., Mandel, S. A., Riederer, P., Miller, R. M., Federoff, H. J., Wullner, U., Papapetropoulos, S., Youdim, M. B., et al. (2010). PGC-1alpha, a potential therapeutic target for early intervention in Parkinson’s disease. Sci Transl Med. https://doi.org/10.1126/scitranslmed.3001059
Zhou, H., Shao, M., Guo, B., Li, C., Lu, Y., Yang, X., ShengnanLi, Li., & H., Zhu, Q., Zhong, H., Wang, Y., Zhang, Z., Lu, J., & Lee, S. M. (2019). Tetramethylpyrazine analogue T-006 promotes the clearance of alpha-synuclein by enhancing proteasome activity in Parkinson’s Disease models. Neurotherapeutics, 16(4), 1225–1236. https://doi.org/10.1007/s13311-019-00759-8
Zivin, J. A. (2007). Clinical trials of neuroprotective therapies. Stroke, 38(2 Suppl), 791–793. https://doi.org/10.1161/01.STR.0000252090.44428.82
Acknowledgements
We thank Prof. Spencer Peter for his critical reading and editing of the manuscript. Many thanks also to Linda Wang for editing the manuscript. We also thank Prof. Yadong Huang (Jinan University, Guangzhou, China) for providing SH-SY5Y cells with stable expression of hA53T mutant α-syn and PC12 cells with Dox-inducible expression of hA53T mutant α-syn.
Funding
This work was partially supported by grants from the National Natural Science Foundation of China (NSFC82073821, 82003726, and 81872842), NSFC (31861163001)-Macau Science and Development Fund (FDCT 0004/2018/AFJ) Cooperative Project, the National Innovative Drug Program of China (2018ZX09301009-001), Scientific Projects of Guangdong Province (2021A0505080012, 2020A1515011060, and 2019A1515110751), and Science and Technology Projects in Guangzhou (202102070001).
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ZJ Z, BJ G, and CY Z designed and performed the experiments and analyzed the data; CY Z and C J participated in experiments with hA53T α-syn transgenic mice PD model. FC L and XL Q performed the transfection assay and immunofluorescence staining studies. XF Y, SM L, HT L, and GX Z directed the project. YW S synthesized TBN. BJ G, ZJ Z, and YQ W oversaw the study design and wrote the manuscript. All authors have read and approved the final manuscript.
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Guo, B., Zheng, C., Cao, J. et al. Tetramethylpyrazine Nitrone Promotes the Clearance of Alpha-Synuclein via Nrf2-Mediated Ubiquitin–Proteasome System Activation. Neuromol Med 26, 9 (2024). https://doi.org/10.1007/s12017-024-08775-4
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DOI: https://doi.org/10.1007/s12017-024-08775-4