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

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.