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
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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