Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan.
Department of Genomic Neurology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan.
Int J Mol Sci. 2021 Jan 1;22(1):400. doi: 10.3390/ijms22010400.
In synucleinopathies, while motor symptoms are thought to be attributed to the accumulation of misfolded α-synuclein (αSyn) in nigral dopaminergic neurons, it remains to be elucidated how cognitive decline arises. Here, we investigated the effects of distinct αSyn strains on cognition and the related neuropathology in the medial septum/diagonal band (MS/DB), a key region for cognitive processing. Bilateral injection of αSyn fibrils into the dorsal striatum potently impaired cognition in mice. The cognitive decline was accompanied by accumulation of phosphorylated αSyn at Ser129 and reduction of gamma-aminobutyric acid (GABA)-ergic but not cholinergic neurons in the MS/DB. Since we have demonstrated that fatty acid-binding protein 3 (FABP3) is critical for αSyn neurotoxicity in nigral dopaminergic neurons, we investigated whether FABP3 also participates in αSyn pathology in the MS/DB and cognitive decline. FABP3 was highly expressed in GABAergic but rarely in cholinergic neurons in the MS/DB. Notably, deletion antagonized the accumulation of phosphorylated αSyn, decrease in GABAergic neurons, and cognitive impairment caused by αSyn fibrils. Overall, the present study indicates that FABP3 mediates αSyn neurotoxicity in septal GABAergic neurons and the resultant cognitive impairment, and that FABP3 in this subpopulation could be a therapeutic target for dementia in synucleinopathies.
在突触核蛋白病中，虽然运动症状被认为归因于黑质多巴胺能神经元中错误折叠的α-突触核蛋白（αSyn）的积累，但认知能力下降的机制仍不清楚。在这里，我们研究了不同的αSyn 菌株对内侧隔核/斜角带（MS/DB）认知的影响，MS/DB 是认知加工的关键区域。αSyn 原纤维向背侧纹状体的双侧注射强烈损害了小鼠的认知能力。认知能力下降伴随着 MS/DB 中磷酸化αSyn 在 Ser129 处的积累和γ-氨基丁酸（GABA）能神经元而不是胆碱能神经元的减少。由于我们已经证明脂肪酸结合蛋白 3（FABP3）在黑质多巴胺能神经元中对αSyn 神经毒性至关重要，因此我们研究了 FABP3 是否也参与了 MS/DB 中的αSyn 病理学和认知能力下降。FABP3 在 MS/DB 中的 GABA 能神经元中高度表达，但在胆碱能神经元中很少表达。值得注意的是，缺失拮抗了 αSyn 纤维引起的磷酸化αSyn 的积累、GABA 能神经元的减少和认知障碍。总的来说，本研究表明 FABP3 介导了 MS/DB 中 GABA 能神经元的αSyn 神经毒性和由此产生的认知障碍，并且该亚群中的 FABP3 可能是突触核蛋白病中痴呆的治疗靶点。
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