Development of an α-synuclein knockdown peptide and evaluation of its efficacy in Parkinson's disease models PMID: 33608634

ADC Targets in Oncology

2026-04-10

Development of an α-synuclein knockdown peptide and evaluation of its efficacy in Parkinson's disease models

Commun Biol. 2021 Feb 19;4(1):232. doi: 10.1038/s42003-021-01746-6.

Jack Wuyang Jin ^# ¹ , Xuelai Fan ^# ¹ , Esther Del Cid-Pellitero ^# ² , Xing-Xing Liu ² , Limin Zhou ³ ⁴ ⁵ ⁶ , Chunfang Dai ³ ⁴ ⁵ ⁶ , Ebrima Gibbs ¹ , Wenting He ³ ⁴ ⁵ ⁶ , Hongjie Li ³ ⁴ ⁵ ⁶ , Xiaobin Wu ³ ⁴ ⁵ ⁶ , Austin Hill ⁷ , Blair R Leavitt ⁷ , Neil Cashman ¹ , Lidong Liu ¹ , Jie Lu ¹ , Thomas M Durcan ² , Zhifang Dong ⁸ ⁹ ¹⁰ ¹¹ , Edward A Fon ¹² , Yu Tian Wang ¹³

Affiliations

1. The Djavad Mowafaghian Centre for Brain Health and Department of Medicine, University of British Columbia, Vancouver, BC, Canada.
2. McGill Parkinson Program, Neurodegenerative Diseases Group, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada.
3. Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.
4. National Clinical Research Center for Child Health and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.
5. China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.
6. Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.
7. Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC, Canada.
8. Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China. [email protected].
9. National Clinical Research Center for Child Health and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China. [email protected].
10. China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China. [email protected].
11. Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China. [email protected].
12. McGill Parkinson Program, Neurodegenerative Diseases Group, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada. [email protected].
13. The Djavad Mowafaghian Centre for Brain Health and Department of Medicine, University of British Columbia, Vancouver, BC, Canada. [email protected].
# Contributed equally.

Abstract

Convincing evidence supports the premise that reducing α-synuclein levels may be an effective therapy for Parkinson's disease (PD); however, there has been lack of a clinically applicable α-synuclein reducing therapeutic strategy. This study was undertaken to develop a blood-brain barrier and plasma membrane-permeable α-synuclein knockdown peptide, Tat-βsyn-degron, that may have therapeutic potential. The peptide effectively reduced the level of α-synuclein via proteasomal degradation both in cell cultures and in Animals. Tat-βsyn-degron decreased α-synuclein aggregates and microglial activation in an α-synuclein pre-formed fibril model of spreading synucleinopathy in transgenic mice overexpressing human A53T α-synuclein. Moreover, Tat-βsyn-degron reduced α-synuclein levels and significantly decreased the parkinsonian toxin-induced neuronal damage and motor impairment in a mouse toxicity model of PD. These results show the promising efficacy of Tat-βsyn-degron in two different animal models of PD and suggest its potential use as an effective PD therapeutic that directly targets the disease-causing process.