Intracellular delivery of Parkin rescues neurons from accumulation of damaged mitochondria and pathological α-synuclein.
Eunna ChungYoungsil ChoiJiae ParkWon Heun NahJaehyung ParkYukdong JungJoonno LeeHyunji LeeSoyoung ParkSun-Young HwangSeongcheol KimJongseok LeeDongjae MinJunghwan JoShinyoung KangMinyong JungPhil Hyu LeeH Earl RuleyDaewoong JoPublished in: Science advances (2020)
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.
Keyphrases
- reactive oxygen species
- binding protein
- poor prognosis
- cell death
- oxidative stress
- protein protein
- spinal cord
- randomized controlled trial
- endoplasmic reticulum
- cell cycle arrest
- signaling pathway
- stem cells
- mouse model
- mesenchymal stem cells
- metabolic syndrome
- cell therapy
- spinal cord injury
- small molecule
- depressive symptoms
- bone marrow