Park SS, Do HA, Park HB, Choi HS, Baek KH

?-synuclein is one of the proteins involved in degenerative neuronal diseases such as Parkinson's disease (PD) or Lewy body dementia (LBD). The pathogenesis is imparted by the abnormal accumulation of ?-synuclein resulting in the formation of a Lewy body (LB) and exerting neurotoxicity via an unknown mechanism. Regulation of ?-synuclein ...

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is achieved by the ubiquitin-proteasome system (UPS), which influences protein homeostasis via inducing proteasome-dependent degradation by attaching a small molecule (ubiquitin) to the substrate. Deubiquitinating enzymes (DUBs) control the UPS by cleaving the peptide or isopeptide bond between ubiquitin and its substrate proteins. In a previous study, we found that YOD1 deubiquitinates and regulates the cellular function of neural precursor cell expressed developmentally down-regulated protein 4 (NEDD4), an E3 ligase that induces ?-synuclein degradation. We hypothesized that YOD1 acts as a DUB involved in a modulated pathway of ?-synuclein. In the current study, we found that YOD1 directly interacts with ?-synuclein and deubiquitinates K6-, K11-, K29-, K33-, and K63-linked polyubiquitin chains on ?-synuclein. Furthermore, YOD1 destabilizes ?-synuclein protein stability by upregulating NEDD4. Collectively, this suggests the possibility that YOD1 is potentially a new regulator in the NEDD4-?-synuclein pathway.

Date: Feb. 19, 2023

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