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[A. Biochemistry/Molecular Biology] A-15

Intracellular Delivery Of Parkin Protects Dopaminergic

Neurons From Mitochondrial Dysfunction And Pathological

α-Synuclein Accumulation

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Sangsun Yoon¹ , Joonno Lee¹ , Dongjae Min¹, Sujeong Kim¹, Seungwoo Lee¹, Sojung Sung¹,
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Eunna Chung¹, Daewoong Jo¹*

¹Neurodegenerative Diseases (NDD) Team, Cellivery Therapeutics, Inc., Seoul 03929, Korea

Parkinson’s disease (PD) is a progressive neurological disorder that leads to shaking, stiffness and difficulty with

walking and balance caused by dopaminergic neuronal damage. Parkin, an E3-ubiquitin ligase, plays a crucial
function for ubiquitination pathway to remove damaged mitochondria and reduce aggregation of pathological α-

Synuclein. Improved Cell-Permeable (iCP) Parkin had been developed as an anti-PD therapeutic agent demonstrating
that iCP-Parkin was delivered into neuron and protects neurons by suppressing accumulation of damaged

mitochondria/pathological α-Synuclein. To achieve mass production of iCP-Parkin as a clinical drug product, protein
structure and manufacturing process of iCP-Parkin have been improved. Structurally optimized iCP-Parkin has been

demonstrated to have auto-ubiquitination activity and cytoprotective activity to repair cells damaged by neurotoxin.
The iCP-Parkin promoted mitophagy and induced expression of mitochondrial proteins such as PGC-1α & NRF1, 2

which are involved in mitochondria biogenesis. In AAV-α-Synuclein-overexpressing cells, the iCP-Parkin suppressed
the accumulation of pathogenic AAV-α-Synuclein. In 6-hydroxydopamine (6-OHDA)-induced & AAV-α-Synuclein-

mediated PD animals, iCP-Parkin recovered motor function in rota-rod (52%, 92%) tests, and thereby increased the
expression of tyrosine hydroxylase (TH) in neurons. These data suggest that iCP-Parkin is structurally stable, and has

a comparable activity to its previous structure, suggesting its potential as a candidate for PD treatment.