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

  • Aging Cell. 2026 Oct;25(10):e70717. doi: 10.1111/acel.70717.
Xuenan Wang  1 ,  Yiru Ding  2  3 ,  Lujuan He  1  2 ,  Xizhi Kang  1  4 ,  Xiwen Geng  5 ,  Fumika Sakaue  6 ,  Takanori Yokota  6 ,  Liang-Wen Zhang  1  4 ,  Wei Yao  7 ,  Ji-Chun Zhang  1  2
Affiliations
  • 1. Institute of Brain Science and Brain-Inspired Research, Shandong Provincial Key Laboratory of Brain Science, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China.
  • 2. Department of Physiology, School of Medicine, Jinan University, Guangzhou, China.
  • 3. NHC Key Laboratory of Mental Health (Peking University), and National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Peking University Sixth Hospital, Peking University Institute of Mental Health, Peking University, Beijing, China.
  • 4. Department of Neurosurgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
  • 5. Key Laboratory of Traditional Chinese Medicine Classical Theory, Ministry of Education, Shandong University of Traditional Chinese Medicine, Jinan, China.
  • 6. Department of Neurology and Neurological Science, Institute of Science Tokyo, Tokyo, China.
  • 7. School of Traditional Chinese Medicine, Jinan University, Guangzhou, China.
PMID: 42775696 DOI: 10.1111/acel.70717
Abstract

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.

Keywords
BDNF–TrkB; Parkinson's disease; antisense oligonucleotide; neuroprotective; α‐Syn.
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