Blood-Derived α-Synuclein Aggregated in the Substantia Nigra of Parabiotic Mice
Abstract
:1. Introduction
2. Materials and Methods
2.1. Animals
2.2. Immunofluorescence (IF)
2.3. Parabiosis Surgery
2.4. Equilibration of the Blood of Parabiotic Partners
2.5. ELISA Test of Hu-α-syn
2.6. Western Blotting
2.7. Dot Blot
2.8. Statistical Analysis
3. Results
3.1. Experimental Design and Feasibility Evaluation
3.2. Alpha-Synuclein Pathology Was Significantly Increased in the SN of Parabiotic WT Mice
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Melki, R. Alpha-synuclein and the prion hypothesis in Parkinson’s disease. Rev. Neurol. 2018, 174, 644–652. [Google Scholar] [CrossRef] [PubMed]
- Mehra, S.; Sahay, S.; Maji, S.K. Alpha-Synuclein misfolding and aggregation: Implications in Parkinson’s disease pathogenesis. Biochim. Biophys. Acta Proteins Proteom. 2019, 1867, 890–908. [Google Scholar] [CrossRef] [PubMed]
- Ganjam, G.K.; Bolte, K.; Matschke, L.A.; Neitemeier, S.; Dolga, A.M.; Hollerhage, M.; Hoglinger, G.U.; Adamczyk, A.; Decher, N.; Oertel, W.H.; et al. Mitochondrial damage by alpha-synuclein causes cell death in human dopaminergic neurons. Cell Death Dis. 2019, 10, 865. [Google Scholar] [CrossRef]
- Vasquez, V.; Mitra, J.; Wang, H.; Hegde, P.M.; Rao, K.S.; Hegde, M.L. A multi-faceted genotoxic network of alpha-synuclein in the nucleus and mitochondria of dopaminergic neurons in Parkinson’s disease: Emerging concepts and challenges. Prog. Neurobiol. 2020, 185, 101729. [Google Scholar] [CrossRef] [PubMed]
- Burre, J.; Sharma, M.; Sudhof, T.C. Cell Biology and Pathophysiology of alpha-Synuclein. Cold Spring Harb. Perspect. Med. 2018, 8, a024091. [Google Scholar] [CrossRef]
- Jankovic, J.; Goodman, I.; Safirstein, B.; Marmon, T.K.; Schenk, D.B.; Koller, M.; Zago, W.; Ness, D.K.; Griffith, S.G.; Grundman, M.; et al. Safety and Tolerability of Multiple Ascending Doses of PRX002/RG7935, an Anti-alpha-Synuclein Monoclonal Antibody, in Patients With Parkinson Disease: A Randomized Clinical Trial. JAMA Neurol. 2018, 75, 1206–1214. [Google Scholar] [CrossRef] [PubMed]
- Killinger, B.A.; Madaj, Z.; Sikora, J.W.; Rey, N.; Haas, A.J.; Vepa, Y.; Lindqvist, D.; Chen, H.; Thomas, P.M.; Brundin, P.; et al. The vermiform appendix impacts the risk of developing Parkinson’s disease. Sci. Transl. Med. 2018, 10, eaar5280. [Google Scholar] [CrossRef] [Green Version]
- Svensson, E.; Horvath-Puho, E.; Thomsen, R.W.; Djurhuus, J.C.; Pedersen, L.; Borghammer, P.; Sorensen, H.T. Vagotomy and subsequent risk of Parkinson’s disease. Ann. Neurol. 2015, 78, 522–529. [Google Scholar] [CrossRef]
- Holmqvist, S.; Chutna, O.; Bousset, L.; Aldrin-Kirk, P.; Li, W.; Bjorklund, T.; Wang, Z.Y.; Roybon, L.; Melki, R.; Li, J.Y. Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats. Acta Neuropathol. 2014, 128, 805–820. [Google Scholar] [CrossRef] [Green Version]
- Peng, C.; Trojanowski, J.Q.; Lee, V.M. Protein transmission in neurodegenerative disease. Nat. Rev. Neurol. 2020, 16, 199–212. [Google Scholar] [CrossRef]
- Wang, R.; Sun, H.; Ren, H.; Wang, G. Alpha-Synuclein aggregation and transmission in Parkinson’s disease: A link to mitochondria and lysosome. Sci. China Life Sci. 2020, 63, 1850–1859. [Google Scholar] [CrossRef] [PubMed]
- Matsumoto, J.; Stewart, T.; Sheng, L.; Li, N.; Bullock, K.; Song, N.; Shi, M.; Banks, W.A.; Zhang, J. Transmission of alpha-synuclein-containing erythrocyte-derived extracellular vesicles across the blood-brain barrier via adsorptive mediated transcytosis: Another mechanism for initiation and progression of Parkinson’s disease? Acta Neuropathol. Commun. 2017, 5, 71. [Google Scholar] [CrossRef] [Green Version]
- Yu, X.; Persillet, M.; Zhang, L.; Zhang, Y.; Xiuping, S.; Li, X.; Ran, G.; Breger, L.S.; Dovero, S.; Porras, G.; et al. Evaluation of blood flow as a route for propagation in experimental synucleinopathy. Neurobiol. Dis. 2021, 150, 105255. [Google Scholar] [CrossRef]
- Ip, C.W.; Klaus, L.C.; Karikari, A.A.; Visanji, N.P.; Brotchie, J.M.; Lang, A.E.; Volkmann, J.; Koprich, J.B. AAV1/2-induced overexpression of A53T-alpha-synuclein in the substantia nigra results in degeneration of the nigrostriatal system with Lewy-like pathology and motor impairment: A new mouse model for Parkinson’s disease. Acta Neuropathol. Commun. 2017, 5, 11. [Google Scholar] [CrossRef] [Green Version]
- Koprich, J.B.; Johnston, T.H.; Reyes, M.G.; Sun, X.; Brotchie, J.M. Expression of human A53T alpha-synuclein in the rat substantia nigra using a novel AAV1/2 vector produces a rapidly evolving pathology with protein aggregation, dystrophic neurite architecture and nigrostriatal degeneration with potential to model the pathology of Parkinson’s disease. Mol. Neurodegener. 2010, 5, 43. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kirik, D.; Annett, L.E.; Burger, C.; Muzyczka, N.; Mandel, R.J.; Bjorklund, A. Nigrostriatal alpha-synucleinopathy induced by viral vector-mediated overexpression of human alpha-synuclein: A new primate model of Parkinson’s disease. Proc. Natl. Acad. Sci. USA 2003, 100, 2884–2889. [Google Scholar] [CrossRef] [Green Version]
- Tanaka, G.; Yamanaka, T.; Furukawa, Y.; Kajimura, N.; Mitsuoka, K.; Nukina, N. Sequence- and seed-structure-dependent polymorphic fibrils of alpha-synuclein. Biochim. Biophys. Acta Mol. Basis Dis. 2019, 1865, 1410–1420. [Google Scholar] [CrossRef]
- Wang, W.; Song, N.; Jia, F.; Tang, T.; Bao, W.; Zuo, C.; Xie, J.; Jiang, H. Genomic DNA levels of mutant alpha-synuclein correlate with non-motor symptoms in an A53T Parkinson’s disease mouse model. Neurochem. Int. 2018, 114, 71–79. [Google Scholar] [CrossRef] [PubMed]
- Kamran, P.; Sereti, K.I.; Zhao, P.; Ali, S.R.; Weissman, I.L.; Ardehali, R. Parabiosis in mice: A detailed protocol. J. Vis. Exp. JoVE 2013, 80, e50556. [Google Scholar] [CrossRef] [Green Version]
- Zhang, S.; Xiao, Q.; Le, W. Olfactory dysfunction and neurotransmitter disturbance in olfactory bulb of transgenic mice expressing human A53T mutant alpha-synuclein. PLoS ONE 2015, 10, e0119928. [Google Scholar] [CrossRef]
- Du, X.Y.; Xie, X.X.; Liu, R.T. The Role of alpha-Synuclein Oligomers in Parkinson’s Disease. Int. J. Mol. Sci. 2020, 21, 8645. [Google Scholar] [CrossRef]
- Karampetsou, M.; Sykioti, V.S.; Leandrou, E.; Melachroinou, K.; Lambiris, A.; Giannelos, A.; Emmanouilidou, E.; Vekrellis, K. Intrastriatal Administration of Exosome-Associated Pathological Alpha-Synuclein Is Not Sufficient by Itself to Cause Pathology Transmission. Front. Neurosci. 2020, 14, 246. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Han, C.; Xiong, N.; Guo, X.; Huang, J.; Ma, K.; Liu, L.; Xia, Y.; Shen, Y.; Li, J.; Jiang, H.; et al. Exosomes from patients with Parkinson’s disease are pathological in mice. J. Mol. Med. 2019, 97, 1329–1344. [Google Scholar] [CrossRef] [PubMed]
- Dohgu, S.; Takata, F.; Matsumoto, J.; Kimura, I.; Yamauchi, A.; Kataoka, Y. Monomeric alpha-synuclein induces blood-brain barrier dysfunction through activated brain pericytes releasing inflammatory mediators in vitro. Microvasc. Res. 2019, 124, 61–66. [Google Scholar] [CrossRef] [PubMed]
- Peelaerts, W.; Bousset, L.; Van der Perren, A.; Moskalyuk, A.; Pulizzi, R.; Giugliano, M.; Van den Haute, C.; Melki, R.; Baekelandt, V. Alpha-Synuclein strains cause distinct synucleinopathies after local and systemic administration. Nature 2015, 522, 340–344. [Google Scholar] [CrossRef]
- Sui, Y.T.; Bullock, K.M.; Erickson, M.A.; Zhang, J.; Banks, W.A. Alpha synuclein is transported into and out of the brain by the blood-brain barrier. Peptides 2014, 62, 197–202. [Google Scholar] [CrossRef] [Green Version]
- Bu, X.L.; Xiang, Y.; Jin, W.S.; Wang, J.; Shen, L.L.; Huang, Z.L.; Zhang, K.; Liu, Y.H.; Zeng, F.; Liu, J.H.; et al. Blood-derived amyloid-beta protein induces Alzheimer’s disease pathologies. Mol. Psychiatry 2018, 23, 1948–1956. [Google Scholar] [CrossRef]
- Chen, L.L.; Wang, Y.B.; Song, J.X.; Deng, W.K.; Lu, J.H.; Ma, L.L.; Yang, C.B.; Li, M.; Xue, Y. Phosphoproteome-based kinase activity profiling reveals the critical role of MAP2K2 and PLK1 in neuronal autophagy. Autophagy 2017, 13, 1969–1980. [Google Scholar] [CrossRef] [Green Version]
- Pupyshev, A.B.; Korolenko, T.A.; Akopyan, A.A.; Amstislavskaya, T.G.; Tikhonova, M.A. Suppression of autophagy in the brain of transgenic mice with overexpression of capital A, Cyrillic53capital TE, Cyrillic-mutant alpha-synuclein as an early event at synucleinopathy progression. Neurosci. Lett. 2018, 672, 140–144. [Google Scholar] [CrossRef]
- Chen, L.; Huang, Y.; Yu, X.; Lu, J.; Jia, W.; Song, J.; Liu, L.; Wang, Y.; Huang, Y.; Xie, J.; et al. Corynoxine Protects Dopaminergic Neurons Through Inducing Autophagy and Diminishing Neuroinflammation in Rotenone-Induced Animal Models of Parkinson’s Disease. Front. Pharmacol. 2021, 12, 642900. [Google Scholar] [CrossRef]
- Chen, L.L.; Huang, Y.J.; Cui, J.T.; Song, N.; Xie, J. Iron Dysregulation in Parkinson’s Disease: Focused on the Autophagy-Lysosome Pathway. ACS Chem. Neurosci. 2019, 10, 863–871. [Google Scholar] [CrossRef] [PubMed]
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Ma, X.; Chen, L.; Song, N.; Qu, L.; Wang, J.; Xie, J. Blood-Derived α-Synuclein Aggregated in the Substantia Nigra of Parabiotic Mice. Biomolecules 2021, 11, 1287. https://doi.org/10.3390/biom11091287
Ma X, Chen L, Song N, Qu L, Wang J, Xie J. Blood-Derived α-Synuclein Aggregated in the Substantia Nigra of Parabiotic Mice. Biomolecules. 2021; 11(9):1287. https://doi.org/10.3390/biom11091287
Chicago/Turabian StyleMa, Xizhen, Leilei Chen, Ning Song, Le Qu, Jun Wang, and Junxia Xie. 2021. "Blood-Derived α-Synuclein Aggregated in the Substantia Nigra of Parabiotic Mice" Biomolecules 11, no. 9: 1287. https://doi.org/10.3390/biom11091287
APA StyleMa, X., Chen, L., Song, N., Qu, L., Wang, J., & Xie, J. (2021). Blood-Derived α-Synuclein Aggregated in the Substantia Nigra of Parabiotic Mice. Biomolecules, 11(9), 1287. https://doi.org/10.3390/biom11091287