The pathological hallmarks of Parkinson’s disease (PD) are the death of dopaminergic neurons in the substantia nigra pars compacta (a region of the midbrain) by the misfolded and accumulated alpha-synuclein proteins.
The cause of PD is still elusive, but various factors appear to play their roles, including genes and environmental factors. Approximately 10% of PD is known to occur by the mutations in one of the specific genes, including SNCA, LRRK2, PARK2, PINK, GBA1, etc.
Parkin, encoded by the PARK2 (also known as PRKN) gene, is the E3-ubiquitin ligase that plays a crucial role in the degradation of proteins such as the misfolded toxic alpha-synucleins.
The mutation in this gene produces defective Parkin proteins, leading to the accumulation of PARkin-Interacting Substrate (PARIS). The accumulated PARIS, in turn, suppresses the activities of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) which is a regulator of mitochondrial metabolism, followed by the aggregation of alpha-synucleins with subsequent neurodegeneration in PD.
Furthermore, the farnesylation (modification of proteins by adding an isoprenyl group to a cysteine residue) of PARIS is also decreased in the substantia nigra of the PD patients, resulting in the increased activities of it. The farnesylation is important to mediate protein-protein interactions.
Therefore, the inhibition of PARIS through the farnesylation is expected to have the therapeutic potentials in PD, by reversing the Parkin-dependent reduction of PGC-1α activities and thereby improving the mitochondrial metabolism.
YEPBIO, headquartered in Anyang, South Korea, is a biotechnology company specialized in developing diagnostics and therapeutics for neurodegenerative diseases. The company, in collaboration with Sungkyunkwan University and Johns Hopkins University, developed its innovative ‘YPD-01 (Farnesol)’ to control the ‘Parkin-Paris-PGC-1α signaling pathway’ via screening 8,320 candidate molecules.
In the murine PD models, YPD-01 inhibited PARIS through the farnesylation and rescued PGC-1α from the repression by PARIS, resulting in the prevention of dopaminergic neuronal loss and behavioral deficits. This research was published in July in the journal ‘Science Translational Medicine’. The company is planning to begin its phase 1 clinical trial of YPD-01 for PD in the latter half of 2022.
Meanwhile, YEPBIO is also developing its novel drugs for Alzheimer’s disease and Huntington’s disease (YND-02), along with the biomarker-based diagnostic kit for PD (YPDBM-01).
Journal Reference
Jo A, Lee Y, Kam TI, Kang SU, Neifert S, Karuppagounder SS, Khang R, Kang H, Park H, Chou SC, Oh S, Jiang H, Swing DA, Ham S, Pirooznia S, Umanah GKE, Mao X, Kumar M, Ko HS, Kang HC, Lee BD, Lee YI, Andrabi SA, Park CH, Lee JY, Kim H, Kim H, Kim H, Cho JW, Paek SH, Na CH, Tessarollo L, Dawson VL, Dawson TM, Shin JH. PARIS farnesylation prevents neurodegeneration in models of Parkinson's disease. Sci Transl Med. 2021 Jul 28;13(604):eaax8891.
https://www.science.org/doi/10.1126/scitranslmed.aax8891
