A Matrigel-based 3D construct of SH-SY5Y cells models the α-synuclein pathologies of Parkinson's disease

Disease Models & Mechanisms

Xiao-Gang Hou¹  Mi-Mi Jin¹  Xiong Zhang¹  Jian-Hong Zhu²  Dong-Yan Hu²  Lei Cui²  Zhao-Feng Li²  Shu-Shu Liu² 

[1] Department of Neurology and Geriatrics, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China;Institute of Nutrition and Diseases, Department of Preventive Medicine, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China;

关键词: parkinson's disease;    3d modeling;    α-synuclein;    lewy body;    dopaminergic neurons;   

DOI  :  10.1242/dmm.049125

来源: DOAJ

【 摘 要 】

Parkinson's disease (PD) is associated with α-synuclein-based Lewy body pathology, which has been difficult to observe in conventional two-dimensional (2D) cell culture and even in animal models. We herein aimed to develop a three-dimensional (3D) cellular model of PD to recapitulate the α-synuclein pathologies. All-trans-retinoic acid-differentiated human SH-SY5Y cells and Matrigel were optimized for 3D construction. The 3D cultured cells displayed higher tyrosine hydroxylase expression than 2D cells and improved dopaminergic-like phenotypes, as suggested by RNA-sequencing analyses. Multiple forms of α-synuclein, including monomer, and low- and high-molecular mass oligomers, were differentially present in the 2D and 3D cells, but mostly remained unchanged upon N-methyl-4-phenyl pyridine or rotenone treatment. Phosphorylated α-synuclein was accumulated, and detergent-insoluble α-synuclein fraction was observed, in the neurotoxin-treated 3D cells. Importantly, Lewy body-like inclusions were captured in the 3D system, including proteinase K-resistant α-synuclein aggregates, ubiquitin aggregation, and β-amyloid and β-sheet protein deposition. The study provides a unique and convenient 3D model of PD that recapitulates critical α-synuclein pathologies and should be useful in multiple PD-associated applications.

【 授权许可】

Unknown