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Eunna Chung1,*, Youngsil Choi1,*, Jiae Park1, Wonheum Nah1, Jaehyung Park1, Yukdong Jung1, Joonno Lee1, Hyunji Lee1, Soyoung Park1, Sunyoung Hwang1, Seongcheol Kim1, Jongseok Lee1, Dongjae Min1, Junghwan Jo1, Shinyoung Kang1, Minyong Jung1, Phil Hyu Lee2, H. Earl Ruley3 and Daewoong Jo1,†
1Cellivery R&D Institute, Cellivery Therapeutics Inc., Seoul 03929, Korea.
2Department of Neurology, Yonsei University College of Medicine, Seoul 120-752, Korea.
3Department of Pathology, Microbiology & Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
†Corresponding author.
*These authors contributed equally to this work
Abstract
Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by mitochondrial dysfunction, Lewy body formation, and loss of dopaminergic neurons. Parkin, an E3 ubiquitin ligase, is thought to inhibit PD progression by removing damaged mitochondria and suppressing the accumulation of α-synuclein and other protein aggregates. The present study describes a protein-based therapy for PD enabled by the development of a cell-permeable Parkin protein (iCP-Parkin) with enhanced solubility and optimized intracellular delivery. iCP-Parkin recovered damaged mitochondria by promoting mitophagy and mitochondrial biogenesis and suppressed toxic accumulations of α-synuclein in cells and animals. Last, iCP-Parkin prevented and reversed declines in tyrosine hydroxylase and dopamine expression concomitant with improved motor function induced by mitochondrial poisons or enforced α-synuclein expression. These results point to common, therapeutically tractable features in PD pathophysiology, and suggest that motor deficits in PD may be reversed, thus providing opportunities for therapeutic intervention after the onset of motor symptoms.
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