Deubiquitinating enzyme YOD1 deubiquitinates and destabilizes α-synuclein.

Sang-Soo Park, Hyeon-Ah Do, Hong-Beom Park, Hae-Seul Choi, Kwang-Hyun Baek

Biochemical and biophysical research communications 2023 Feb 19

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α-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 α-synuclein resulting in the formation of a Lewy body (LB) and exerting neurotoxicity via an unknown mechanism. Regulation of α-synuclein 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 α-synuclein degradation. We hypothesized that YOD1 acts as a DUB involved in a modulated pathway of α-synuclein. In the current study, we found that YOD1 directly interacts with α-synuclein and deubiquitinates K6-, K11-, K29-, K33-, and K63-linked polyubiquitin chains on α-synuclein. Furthermore, YOD1 destabilizes α-synuclein protein stability by upregulating NEDD4. Collectively, this suggests the possibility that YOD1 is potentially a new regulator in the NEDD4-α-synuclein pathway. Copyright © 2023 Elsevier Inc. All rights reserved.

Citation

Sang-Soo Park, Hyeon-Ah Do, Hong-Beom Park, Hae-Seul Choi, Kwang-Hyun Baek. Deubiquitinating enzyme YOD1 deubiquitinates and destabilizes α-synuclein. Biochemical and biophysical research communications. 2023 Feb 19;645:124-131