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bioRxiv · 10.1101/2022.08.17.504224

UBA52 is crucial in HSP90 ubiquitylation and neurodegenerative signaling during early phase of Parkinson disease

Tiwari, S.·Singh, A.·Gupta, P.·SINGH, S.
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Abstract

Protein aggregation is one of the major pathological events in age-related Parkinsons 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 the early phase of PD pathology. Wild-type human Myc--synuclein transfected neurons, -synuclein-PFFs treated cells, rotenone-induced sporadic models of PD and SNCA C57BL/6J-Tg (Th-SNCA*A30P*A53T)39 Eric/J transgenic mice showed downregulated level 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 strong interaction of UBA52 with -synuclein, HSP90 and E3-ubiquitin ligase CHIP, besides its co-localization with -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 exhibited the downregulated -synuclein protein abundance with increased TH and restored proteasome activity during the diseased condition. Furthermore, Myc-UBA52 expression inhibited the augmented HSP90 protein level along with its various client proteins, HSP75 (homologue of HSP90 in mitochondrion) and ER stress-related markers during early PD. Taken together, 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.

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Tiwari, S., Singh, A., Gupta, P., SINGH, S.. 2022-08-17. UBA52 is crucial in HSP90 ubiquitylation and neurodegenerative signaling during early phase of Parkinson disease. https://doi.org/10.1101/2022.08.17.504224

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