Department of Neurology, Technische Universität Dresden, 01307 Dresden, Germany.
Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), 01307 Dresden, Germany.
Biomolecules. 2024 Jun 25;14(7):756. doi: 10.3390/biom14070756.
Aggregation of the protein α-Synuclein (αSyn) is a hallmark of Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple systems atrophy, and alleviating the extent of αSyn pathology is an attractive strategy against neurodegeneration. The engineered binding protein β-wrapin AS69 binds monomeric αSyn. AS69 reduces primary and secondary nucleation as well as fibril elongation in vitro. It also mitigates aSyn pathology in a mouse model based on intrastriatal injection of aSyn pre-formed fibrils (PFFs). Since the PFF-based model does not represent all aspects of PD, we tested here whether AS69 can reduce neurodegeneration resulting from αSyn overexpression. Human A53T-αSyn was overexpressed in the mouse Substantia nigra (SN) by using recombinant adeno-associated viral vector (rAAV). AS69 was also expressed by rAAV transduction. Behavioral tests and immunofluorescence staining were used as outcomes. Transduction with rAAV-αSyn resulted in αSyn pathology as reported by phospho-αSyn staining and caused degeneration of dopaminergic neurons in the SN. The co-expression of rAAV-AS69 did not reduce αSyn pathology or the degeneration of dopaminergic neurons. We conclude that αSyn monomer binding by rAAV-AS69 was insufficient to protect from aSyn pathology resulting from αSyn overexpression.
蛋白α-突触核蛋白（αSyn）的聚集是帕金森病（PD）、路易体痴呆（DLB）和多系统萎缩的标志，减轻αSyn 病理学的程度是对抗神经退行性变的一种有吸引力的策略。工程化的结合蛋白 β-wrapin AS69 结合单体 αSyn。AS69 在体外减少初级和次级成核以及原纤维伸长。它还减轻了基于纹状体注射αSyn 预形成纤维（PFF）的小鼠模型中的αSyn 病理学。由于基于 PFF 的模型不能代表 PD 的所有方面，我们在这里测试了 AS69 是否可以减少由于 αSyn 过表达导致的神经退行性变。通过使用重组腺相关病毒载体（rAAV）在小鼠黑质（SN）中过表达人 A53T-αSyn。rAAV 转导也表达 AS69。行为测试和免疫荧光染色用作结果。rAAV-αSyn 的转导导致磷酸化-αSyn 染色报告的 αSyn 病理学，并导致 SN 中的多巴胺能神经元变性。rAAV-AS69 的共表达并没有减少 αSyn 病理学或多巴胺能神经元的变性。我们得出结论，rAAV-AS69 对 αSyn 单体的结合不足以防止由 αSyn 过表达引起的 αSyn 病理学。
