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

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.

• Authors: 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
• Journal: Molecular therapy. Nucleic acids (Mol Ther Nucleic Acids) Vol. 29 Pg. 1-15 (Sep 13 2022) ISSN: 2162-2531 [Print] United States
• PMID: 35784012 (Publication Type: Journal Article)
• Copyright: © 2022 The Author(s).