| First Author | Tiwari S | Year | 2022 |
| Journal | Cells | Volume | 11 |
| Issue | 23 | PubMed ID | 36497031 |
| Mgi Jnum | J:346174 | Mgi Id | MGI:7408904 |
| Doi | 10.3390/cells11233770 | Citation | Tiwari S, et al. (2022) UBA52 Is Crucial in HSP90 Ubiquitylation and Neurodegenerative Signaling during Early Phase of Parkinson's Disease. Cells 11(23) |
| abstractText | Protein aggregation is one of the major pathological events in age-related Parkinson's disease (PD) pathology, predominantly regulated by the ubiquitin-proteasome system (UPS). UPS essentially requires core component ubiquitin; however, its role in PD pathology is obscure. This study aimed to investigate the role of ubiquitin-encoding genes in sporadic PD pathology. Both cellular and rat models of PD as well as SNCA C57BL/6J-Tg (Th-SNCA*A30P*A53T)39 Eric/J transgenic mice showed a decreased abundance of UBA52 in conjunction with significant downregulation of tyrosine hydroxylase (TH) and neuronal death. In silico predictions, mass spectrometric analysis, and co-immunoprecipitation findings suggested the protein-protein interaction of UBA52 with alpha-synuclein, HSP90 and E3-ubiquitin ligase CHIP, and its co-localization with alpha-synuclein in the mitochondrion. Next, in vitro ubiquitylation assay indicated an imperative requirement of the lysine-63 residue of UBA52 in CHIP-mediated HSP90 ubiquitylation. Myc-UBA52 expressed neurons inhibited alteration in PD-specific markers such as alpha-synuclein and TH protein along with increased proteasome activity in diseased conditions. Furthermore, Myc-UBA52 expression inhibited the altered protein abundance of HSP90 and its various client proteins, HSP75 (homolog of HSP90 in mitochondrion) and ER stress-related markers during early PD. Taken together, the data highlights the critical role of UBA52 in HSP90 ubiquitylation in parallel to its potential contribution to the modulation of various disease-related neurodegenerative signaling targets during the early phase of PD pathology. |
