TY - JOUR
T1 - Suppression of α-synuclein propagation after intrastriatal injection in FABP3 null mice
AU - Matsuo, Kazuya
AU - Kawahata, Ichiro
AU - Melki, Ronald
AU - Bousset, Luc
AU - Owada, Yuji
AU - Fukunaga, Kohji
N1 - Funding Information:
This work was supported by the Project of Translational and Clinical Research Core Centers from the Japan Agency for Medical Research and Development (AMED) [JP19dm0107071 and JP20dm0107071 to K.F.] and grants-in-aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan (18J20651 to K.M.).
Publisher Copyright:
© 2021 Elsevier B.V.
PY - 2021/6/1
Y1 - 2021/6/1
N2 - Accumulation and aggregation of α-synuclein (αSyn) trigger neuronal loss in the substantia nigra pars compacta (SNpc), which in turn causes motor symptoms in Parkinson's disease. We previously demonstrated that fatty acid-binding protein 3 (FABP3), an intracellular fatty acid carrier protein, enhances αSyn neurotoxicity in SNpc and motor impairments after intranigral injection of αSyn fibrils. However, the temporal profile of αSyn fibril spread and their toxicity remains unclear. In the present study, we investigated the temporal profile of αSyn fibril spread and its toxicity, which induces intracellular fibril formation. Monomeric and fibrillar aSyn assemblies were labeled with ATTO550 to distinguish the exogenous form from the endogenous species and injected into bilateral striatum in Fabp3+/+ (wild type) and Fabp3-/- mice. Accumulation of both monomeric and fibrillar exogenous αSyn in the SNpc was drastically decreased in Fabp3-/- mice compared to that in the Fabp3+/+ counterparts. Deletion of Fabp3 also prevented exogenous αSyn fibril-induced seeding of the endogenous αSyn into aggregates containing phosphorylated and filamentous forms in the SNpc. Consistent with these results, loss of dopaminergic neurons and subsequent impaired motor behavior were attenuated in Fabp3-/- mice. These results highlight the crucial role of FABP3 in pathogenic αSyn accumulation and its seeding ability. Taken together, FABP3 could be a potential therapeutic target against αSyn propagation in synucleinopathies.
AB - Accumulation and aggregation of α-synuclein (αSyn) trigger neuronal loss in the substantia nigra pars compacta (SNpc), which in turn causes motor symptoms in Parkinson's disease. We previously demonstrated that fatty acid-binding protein 3 (FABP3), an intracellular fatty acid carrier protein, enhances αSyn neurotoxicity in SNpc and motor impairments after intranigral injection of αSyn fibrils. However, the temporal profile of αSyn fibril spread and their toxicity remains unclear. In the present study, we investigated the temporal profile of αSyn fibril spread and its toxicity, which induces intracellular fibril formation. Monomeric and fibrillar aSyn assemblies were labeled with ATTO550 to distinguish the exogenous form from the endogenous species and injected into bilateral striatum in Fabp3+/+ (wild type) and Fabp3-/- mice. Accumulation of both monomeric and fibrillar exogenous αSyn in the SNpc was drastically decreased in Fabp3-/- mice compared to that in the Fabp3+/+ counterparts. Deletion of Fabp3 also prevented exogenous αSyn fibril-induced seeding of the endogenous αSyn into aggregates containing phosphorylated and filamentous forms in the SNpc. Consistent with these results, loss of dopaminergic neurons and subsequent impaired motor behavior were attenuated in Fabp3-/- mice. These results highlight the crucial role of FABP3 in pathogenic αSyn accumulation and its seeding ability. Taken together, FABP3 could be a potential therapeutic target against αSyn propagation in synucleinopathies.
KW - Dopaminergic neurons
KW - FABP3
KW - Lewy body disease
KW - α-Synuclein
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U2 - 10.1016/j.brainres.2021.147383
DO - 10.1016/j.brainres.2021.147383
M3 - Article
C2 - 33636166
AN - SCOPUS:85101849923
SN - 0006-8993
VL - 1760
JO - Brain Research
JF - Brain Research
M1 - 147383
ER -