Novel DNA Aptamers for Parkinson's Disease Treatment Inhibit α-Synuclein Aggregation and Facilitate its Degradation

Yuan Zheng; Jing Qu; Fenqin Xue; Yan Zheng; Bo Yang; Yongchang Chang; Hui Yang; Jianliang Zhang

doi:10.1016/j.omtn.2018.02.011

Novel DNA Aptamers for Parkinson's Disease Treatment Inhibit α-Synuclein Aggregation and Facilitate its Degradation

Mol Ther Nucleic Acids. 2018 Jun 1:11:228-242. doi: 10.1016/j.omtn.2018.02.011. Epub 2018 Mar 6.

Authors

Yuan Zheng¹, Jing Qu¹, Fenqin Xue², Yan Zheng³, Bo Yang⁴, Yongchang Chang⁵, Hui Yang¹, Jianliang Zhang⁶

Affiliations

¹ Department of Neurobiology, Beijing Institute of Brain Disorders, Capital Medical University, Key Laboratory for Neurodegenerative Disease of the Ministry of Education, Beijing Center of Neural Regeneration and Repair, Beijing 100069, China.
² Core Facilities Center, Capital Medical University, Beijing 100069, China.
³ Department of Physiology, Capital Medical University, Beijing 100069, China.
⁴ School of Life Sciences, Nantong University, Nantong, Jiangsu 226001, China.
⁵ Division of Neurobiology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, 85013, USA.
⁶ Department of Neurobiology, Beijing Institute of Brain Disorders, Capital Medical University, Key Laboratory for Neurodegenerative Disease of the Ministry of Education, Beijing Center of Neural Regeneration and Repair, Beijing 100069, China. Electronic address: jlzhang@ccmu.edu.cn.

Abstract

Parkinson's disease (PD) is one of the most prevalent forms of synucleinopathies, and it is characterized neuropathologically by the presence of intracellular inclusions composed primarily of the protein α-synuclein (α-syn) in neurons. The previous immunotherapy targeting the α-syn in PD models with monoclonal antibodies has established α-syn protein as an effective target for neuronal cell death. However, due to the essential weaknesses of antibody and the unique features of aptamers, the aptamers could represent a promising alternative to the currently used antibodies in immunotherapy for PD. In this study, the purified human α-syn was used as the target for in vitro selection of aptamers using systematic evolution by exponential enrichment. This resulted in the identification of two 58-base DNA aptamers with a high binding affinity and good specificity to the α-syn, with K_D values in the nanomolar range. Both aptamers could effectively reduce α-syn aggregation in vitro and in cells and target the α-syn to intracellular degradation through the lysosomal pathway. These effects consequently rescued the mitochondrial dysfunction and cellular defects caused by α-syn overexpression. To our knowledge, this is the first study to employ aptamers to block the aberrant cellular effects of the overexpressed α-syn in cells.

Keywords: Parkinson’s disease; aptamer; immunotherapy; α-synuclein.