Suppression of abnormal α-synuclein expression by activation of BDNF transcription ameliorates Parkinson's disease-like pathology

Qianqian Cao; Shilin Luo; Wei Yao; Youge Qu; Nanbu Wang; Jian Hong; Shigeo Murayama; Zhentao Zhang; Jiaxu Chen; Kenji Hashimoto; Qi Qi; Ji-Chun Zhang

doi:10.1016/j.omtn.2022.05.037

Suppression of abnormal α-synuclein expression by activation of BDNF transcription ameliorates Parkinson's disease-like pathology

Mol Ther Nucleic Acids. 2022 Jun 1:29:1-15. doi: 10.1016/j.omtn.2022.05.037. eCollection 2022 Sep 13.

Authors

Qianqian Cao^{1

2}, Shilin Luo³, Wei Yao⁴, Youge Qu⁵, Nanbu Wang⁶, Jian Hong⁷, Shigeo Murayama⁸, Zhentao Zhang⁹, Jiaxu Chen⁴, Kenji Hashimoto⁵, Qi Qi¹⁰, Ji-Chun Zhang¹

Affiliations

¹ Department of Physiology, School of Medicine, Jinan University, Guangzhou 510632, China.
² Department of Nuclear Medicine, The First Affiliated Hospital of Jinan University, Guangzhou, China.
³ Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha 410011, China.
⁴ Guangzhou Key Laboratory of Formula-pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou 510632, China.
⁵ Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, 260-8670 Chiba, Japan.
⁶ The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510632, China.
⁷ Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou 510632, China.
⁸ Department of Neuropathology (Brain Bank for Aging Research), Tokyo Metropolitan Geriatric Hospital & Institute of Gerontology, Tokyo 173-0015, Japan.
⁹ Department of Neurology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
¹⁰ MOE Key Laboratory of Tumor Molecular Biology, Clinical Translational Center for Targeted Drug, Department of Pharmacology, School of Medicine, Jinan University, Guangzhou 510632, China.

Abstract

Parkinson's disease (PD) is characterized by the formation of Lewy bodies (LBs) in the brain. LBs are mainly composed of phosphorylated and aggregated α-synuclein (α-Syn). Thus, strategies to reduce the expression of α-Syn offer promising therapeutic avenues for PD. DNA/RNA heteroduplex oligonucleotides (HDOs) are a novel technology for gene silencing. Using an α-Syn-HDO that specifically targets α-Syn, we examined whether α-Syn-HDO attenuates pathological changes in the brain of mouse models of PD. Overexpression of α-Syn induced dopaminergic neuron degeneration through inhibition of cyclic AMP-responsive-element-binding protein (CREB) and activation of methyl CpG binding protein 2 (MeCP2), resulting in brain-derived neurotrophic factor (BDNF) downregulation. α-Syn-HDO exerted a more potent silencing effect on α-Syn than α-Syn-antisense oligonucleotides (ASOs). α-Syn-HDO attenuated abnormal α-Syn expression and ameliorated dopaminergic neuron degeneration via BDNF upregulation by activation of CREB and inhibition of MeCP2. These findings demonstrated that inhibition of α-Syn by α-Syn-HDO protected against dopaminergic neuron degeneration via activation of BDNF transcription. Therefore, α-Syn-HDO may serve as a new therapeutic agent for PD.

Keywords: BDNF; MT: Oligonucleotides; Parkinson’s disease; Therapies and Applications; alpha-synuclein; oligonucleotide; transcription.