Fatty Acid Binding Protein 3 Enhances the Spreading and Toxicity of α-Synuclein in Mouse Brain
Autor: | Yasushi Yabuki, Yasushi Kawata, Kazuya Matsuo, Naoya Fukui, Kohji Fukunaga, Tomohiro Mizobata, Yuji Owada, Norifumi Shioda, Ichiro Kawahata |
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Jazyk: | angličtina |
Rok vydání: | 2020 |
Předmět: |
Synucleinopathies
animal diseases Fluorescent Antibody Technique environment and public health lcsh:Chemistry Mice Cognition heterocyclic compounds Phosphorylation lcsh:QH301-705.5 Spectroscopy Mice Knockout Neurons Chemistry Brain General Medicine Ligand (biochemistry) Immunohistochemistry α-synucleinopathy Computer Science Applications Toxicity alpha-Synuclein medicine.medical_specialty Tyrosine 3-Monooxygenase α-synuclein propagation Substantia nigra Catalysis Article Inorganic Chemistry α-synuclein Internal medicine medicine Animals Humans Physical and Theoretical Chemistry Molecular Biology Tyrosine hydroxylase fatty acid binding protein 3 Pars compacta Dementia with Lewy bodies Organic Chemistry medicine.disease nervous system diseases Disease Models Animal Endocrinology nervous system lcsh:Biology (General) lcsh:QD1-999 Fatty Acid Binding Protein 3 |
Zdroj: | International Journal of Molecular Sciences, Vol 21, Iss 6, p 2230 (2020) International Journal of Molecular Sciences Volume 21 Issue 6 |
ISSN: | 1422-0067 |
Popis: | Oligomerization and/or aggregation of &alpha synuclein (&alpha Syn) triggers &alpha synucleinopathies such as Parkinson&rsquo s disease and dementia with Lewy bodies. It is known that &alpha Syn can spread in the brain like prions however, the mechanism remains unclear. We demonstrated that fatty acid binding protein 3 (FABP3) promotes propagation of &alpha Syn in mouse brain. Animals were injected with mouse or human &alpha Syn pre-formed fibrils (PFF) into the bilateral substantia nigra pars compacta (SNpc). Two weeks after injection of mouse &alpha Syn PFF, wild-type (WT) mice exhibited motor and cognitive deficits, whereas FABP3 knock-out (Fabp3&minus /&minus ) mice did not. The number of phosphorylated &alpha Syn (Ser-129)-positive cells was significantly decreased in Fabp3&minus mouse brain compared to that in WT mice. The SNpc was unilaterally infected with AAV-GFP/FABP3 in Fabp3&minus mice to confirm the involvement of FABP3 in the development of &alpha Syn PFF toxicity. The number of tyrosine hydroxylase (TH)- and phosphorylated &alpha Syn (Ser-129)-positive cells following &alpha Syn PFF injection significantly decreased in Fabp3&minus mice and markedly increased by AAV-GFP/FABP3 infection. Finally, we confirmed that the novel FABP3 inhibitor MF1 significantly antagonized motor and cognitive impairments by preventing &alpha Syn spreading following &alpha Syn PFF injection. Overall, FABP3 enhances &alpha Syn spreading in the brain following &alpha Syn PFF injection, and the FABP3 ligand MF1 represents an attractive therapeutic candidate for &alpha synucleinopathy. |
Databáze: | OpenAIRE |
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