Inhibition of Abnormal Elevated α-Synuclein Ameliorates Dopaminergic Neuron Degeneration in Parkinson's Disease Mouse Model.

Parkinson's disease (PD) is characterized by the accumulation of Lewy bodies (LBs) in the brain, predominantly consisting of aggregated and phosphorylated α-synuclein (α-Syn). Consequently, strategies to suppress α-Syn expression offer substantial therapeutic potential for PD. This study explores heteroduplex oligonucleotides (HDOs), an innovative gene-silencing technology utilizing DNA/RNA or DNA/DNA hybrids. We designed two HDOs targeting α-Syn: α-Syn-HDO-1 (DNA/RNA) and α-Syn-HDO-2 (DNA/DNA). Both demonstrated robust silencing of α-Syn expression in mice. In AAV-hSyn-human SNCA-treated mice, these α-Syn-HDOs exerted neuroprotective effects on dopaminergic neurons. Furthermore, they reduced aberrant α-Syn accumulation in α-Syn-HEK293 cells and in mice treated with α-Syn preformed fibrils (PFFs). The neuroprotective effects of α-Syn-HDOs were linked to activation of the brain-derived neurotrophic factor (BDNF)-tyrosine kinase B (TrkB) signaling pathway. Moreover, BDNF overexpression diminished abnormal α-Syn aggregation in both PFFs-treated α-Syn-HEK293 cells and PFFs-treated mice. These results highlight the capacity of α-Syn-HDOs to protect dopaminergic neurons by enhancing BDNF-TrkB signaling through the inhibition of abnormal elevated α-Syn. Our findings position α-Syn-HDOs as promising therapeutic candidates for PD and suggest BDNF as a potential diagnostic biomarker or indicator of treatment efficacy.