| First Author | Schorova L | Year | 2023 |
| Journal | NPJ Parkinsons Dis | Volume | 9 |
| Issue | 1 | Pages | 157 |
| PubMed ID | 38017009 | Mgi Jnum | J:350136 |
| Mgi Id | MGI:7661210 | Doi | 10.1038/s41531-023-00601-1 |
| Citation | Schorova L, et al. (2023) USP19 deubiquitinase inactivation regulates alpha-synuclein ubiquitination and inhibits accumulation of Lewy body-like aggregates in mice. NPJ Parkinsons Dis 9(1):157 |
| abstractText | The USP19 deubiquitinase is found in a locus associated with Parkinson's Disease (PD), interacts with chaperonins, and promotes secretion of alpha-synuclein (alpha-syn) through the misfolding-associated protein secretion (MAPS) pathway. Since these processes might modulate the processing of alpha-syn aggregates in PD, we inactivated USP19 (KO) in mice expressing the A53T mutation of alpha-syn and in whom alpha-syn preformed fibrils (PFF) had been injected in the striatum. Compared to WT, KO brains showed decreased accumulation of phospho-synuclein (pSyn) positive aggregates. This improvement was associated with less activation of microglia and improved performance in a tail-suspension test. Exposure of primary neurons from WT and KO mice to PFF in vitro also led to decreased accumulation of pSyn aggregates. KO did not affect uptake of PFF nor propagation of aggregates in the cultured neurons. We conclude that USP19 instead modulates intracellular dynamics of aggregates. At an early time following PFF injection when the number of pSyn-positive neurons were similar in WT and KO brains, the KO neurons contained less aggregates. KO brain aggregates stained more intensely with anti-ubiquitin antibodies. Immunoprecipitation of soluble proteins from WT and KO brains with antibodies to pSyn showed higher levels of ubiquitinated oligomeric species in the KO samples. We propose that the improved pathology in USP19 KO brains may arise from decreased formation or enhanced clearance of the more ubiquitinated aggregates and/or enhanced disassembly towards more soluble oligomeric species. USP19 inhibition may represent a novel therapeutic approach that targets the intracellular dynamics of alpha-syn complexes. |
