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Structurally distinct α-synuclein fibrils induce robust parkinsonian pathology.
Mov Disord. 2020 02; 35(2):256-267.MD

Abstract

OBJECTIVE

Alpha-synuclein (α-syn) is a major component of Lewy bodies, which are the pathological hallmark in Parkinson's disease, and its genetic mutations cause familial forms of Parkinson's disease. Patients with α-syn G51D mutation exhibit severe clinical symptoms. However, in vitro studies showed low propensity for α-syn with the G51D mutation. We studied the mechanisms associated with severe neurotoxicity of α-syn G51D mutation using a murine model generated by G51D α-syn fibril injection into the brain.

METHODS

Structural analysis of wild-type and G51D α-syn-fibrils were performed using Fourier transform infrared spectroscopy. The ability of α-syn fibrils forming aggregates was first assessed in in vitro mammalian cells. An in vivo mouse model with an intranigral injection of α-syn fibrils was then used to evaluate the propagation pattern of α-syn and related cellular changes.

RESULTS

We found that G51D α-syn fibrils have higher β-sheet contents than wild-type α-syn fibrils. The addition of G51D α-syn fibrils to mammalian cells overexpressing α-syn resulted in the formation of phosphorylated α-syn inclusions at a higher rate. Similarly, an injection of G51D α-syn fibrils into the substantia nigra of a mouse brain induced more widespread phosphorylated α-syn pathology. Notably, the mice injected with G51D α-syn fibrils exhibited progressive nigral neuronal loss accompanied with mitochondrial abnormalities and motor impairment.

CONCLUSION

Our findings indicate that the structural difference of G51D α-syn fibrils plays an important role in the rapidly developed and more severe neurotoxicity of G51D mutation-linked Parkinson's disease. © 2019 International Parkinson and Movement Disorder Society.

Links

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Authors+Show Affiliations

Hayakawa H
Department of Neurology, Osaka University Graduate School of Medicine, Osaka, Japan.
Nakatani R
Department of Neurology, Osaka University Graduate School of Medicine, Osaka, Japan.
Ikenaka K
Department of Neurology, Osaka University Graduate School of Medicine, Osaka, Japan.
Aguirre C
Institute of Protein Research, Osaka University, Osaka, Japan.
Choong CJ
Department of Neurology, Osaka University Graduate School of Medicine, Osaka, Japan.
Tsuda H
Department of Neurology, Osaka University Graduate School of Medicine, Osaka, Japan.
Nagano S
Department of Neurology, Osaka University Graduate School of Medicine, Osaka, Japan.
Koike M
Department of Cell Biology and Neuroscience, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Ikeuchi T
Department of Molecular Genetics, Bioresource Science Branch, Center for Bioresources, Brain Research Institute, Niigata University, Niigata, Japan.
Hasegawa M
Department of Neuropathology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
Papa SM
Department of Neurology, Emory University School of Medicine, Atlanta, Georgia, USA.
Nagai Y
Department of Neurology, Osaka University Graduate School of Medicine, Osaka, Japan. Department of Neurotherapeutics, Osaka University Graduate School of Medicine, Osaka, Japan.
Mochizuki H
Department of Neurology, Osaka University Graduate School of Medicine, Osaka, Japan.
Baba K
Department of Neurology, Osaka University Graduate School of Medicine, Osaka, Japan.

MeSH

AnimalsBrainHumansInclusion BodiesLewy BodiesMaleMice, Inbred C57BLMutationParkinson DiseasePhosphorylationSubstantia Nigraalpha-Synuclein

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31643109

Citation

Hayakawa, Hideki, et al. "Structurally Distinct Α-synuclein Fibrils Induce Robust Parkinsonian Pathology." Movement Disorders : Official Journal of the Movement Disorder Society, vol. 35, no. 2, 2020, pp. 256-267.
Hayakawa H, Nakatani R, Ikenaka K, et al. Structurally distinct α-synuclein fibrils induce robust parkinsonian pathology. Mov Disord. 2020;35(2):256-267.
Hayakawa, H., Nakatani, R., Ikenaka, K., Aguirre, C., Choong, C. J., Tsuda, H., Nagano, S., Koike, M., Ikeuchi, T., Hasegawa, M., Papa, S. M., Nagai, Y., Mochizuki, H., & Baba, K. (2020). Structurally distinct α-synuclein fibrils induce robust parkinsonian pathology. Movement Disorders : Official Journal of the Movement Disorder Society, 35(2), 256-267. https://doi.org/10.1002/mds.27887
Hayakawa H, et al. Structurally Distinct Α-synuclein Fibrils Induce Robust Parkinsonian Pathology. Mov Disord. 2020;35(2):256-267. PubMed PMID: 31643109.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Structurally distinct α-synuclein fibrils induce robust parkinsonian pathology. AU - Hayakawa,Hideki, AU - Nakatani,Rie, AU - Ikenaka,Kensuke, AU - Aguirre,Cesar, AU - Choong,Chi-Jing, AU - Tsuda,Hiroshi, AU - Nagano,Seiichi, AU - Koike,Masato, AU - Ikeuchi,Takeshi, AU - Hasegawa,Masato, AU - Papa,Stella M, AU - Nagai,Yoshitaka, AU - Mochizuki,Hideki, AU - Baba,Kousuke, Y1 - 2019/10/23/ PY - 2019/05/16/received PY - 2019/07/24/revised PY - 2019/08/26/accepted PY - 2019/10/24/pubmed PY - 2021/1/16/medline PY - 2019/10/24/entrez KW - Lewy body KW - Parkinson's disease KW - alpha-synuclein KW - animal model KW - propagation SP - 256 EP - 267 JF - Movement disorders : official journal of the Movement Disorder Society JO - Mov Disord VL - 35 IS - 2 N2 - OBJECTIVE: Alpha-synuclein (α-syn) is a major component of Lewy bodies, which are the pathological hallmark in Parkinson's disease, and its genetic mutations cause familial forms of Parkinson's disease. Patients with α-syn G51D mutation exhibit severe clinical symptoms. However, in vitro studies showed low propensity for α-syn with the G51D mutation. We studied the mechanisms associated with severe neurotoxicity of α-syn G51D mutation using a murine model generated by G51D α-syn fibril injection into the brain. METHODS: Structural analysis of wild-type and G51D α-syn-fibrils were performed using Fourier transform infrared spectroscopy. The ability of α-syn fibrils forming aggregates was first assessed in in vitro mammalian cells. An in vivo mouse model with an intranigral injection of α-syn fibrils was then used to evaluate the propagation pattern of α-syn and related cellular changes. RESULTS: We found that G51D α-syn fibrils have higher β-sheet contents than wild-type α-syn fibrils. The addition of G51D α-syn fibrils to mammalian cells overexpressing α-syn resulted in the formation of phosphorylated α-syn inclusions at a higher rate. Similarly, an injection of G51D α-syn fibrils into the substantia nigra of a mouse brain induced more widespread phosphorylated α-syn pathology. Notably, the mice injected with G51D α-syn fibrils exhibited progressive nigral neuronal loss accompanied with mitochondrial abnormalities and motor impairment. CONCLUSION: Our findings indicate that the structural difference of G51D α-syn fibrils plays an important role in the rapidly developed and more severe neurotoxicity of G51D mutation-linked Parkinson's disease. © 2019 International Parkinson and Movement Disorder Society. SN - 1531-8257 UR - https://www.unboundmedicine.com/medline/citation/31643109/Structurally_distinct_α_synuclein_fibrils_induce_robust_parkinsonian_pathology_ DB - PRIME DP - Unbound Medicine ER -