Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan.
CEA, Institut François Jacob (MIRcen) and CNRS, Laboratory of Neurodegenerative Diseases, 18 Route du Panorama, 92265 Fontenay-aux-Roses, France.
Brain Res. 2021 Jun 1;1760:147383. doi: 10.1016/j.brainres.2021.147383. Epub 2021 Feb 24.
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.
α-突触核蛋白（αSyn）的积累和聚集引发黑质致密部（SNpc）神经元的丢失，进而导致帕金森病的运动症状。我们之前的研究表明，细胞内脂肪酸载体蛋白脂肪酸结合蛋白 3（FABP3）增强了 SNpc 中的αSyn 神经毒性，以及 αSyn 纤维注射后运动功能的损伤。然而，αSyn 纤维的扩散及其毒性的时间进程尚不清楚。在本研究中，我们研究了αSyn 纤维的扩散及其毒性的时间进程，该毒性诱导细胞内纤维的形成。单体和纤维状的 aSyn 组装体用 ATTO550 标记，以区分外源性形式和内源性物质，并注入 Fabp3（野生型）和 Fabp3 小鼠的双侧纹状体。与 Fabp3 对应物相比，Fabp3 小鼠 SNpc 中单体和纤维状外源性αSyn 的积累明显减少。Fabp3 的缺失也阻止了外源性αSyn 纤维诱导内源性αSyn 聚集到含有磷酸化和丝状形式的聚集体中。这些结果与以下结果一致：多巴胺能神经元的丢失和随后运动行为的损伤在 Fabp3 小鼠中减轻。这些结果突出了 FABP3 在致病性αSyn 积累及其种子能力中的关键作用。总之，FABP3 可能是针对突触核蛋白病中αSyn 传播的潜在治疗靶点。
