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
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.