Impairment of protein degradation and proteasome function in hereditary neuropathies

Glia
Jordan J S VerPlankL Wrabetz

Abstract

In several neurodegenerative diseases in which misfolded proteins accumulate there is impairment of the ubiquitin proteasome system (UPS). We tested if a similar disruption of proteostasis occurs in hereditary peripheral neuropathies. In sciatic nerves from mouse models of two human neuropathies, Myelin Protein Zero mutation (S63del) and increased copy number (P0 overexpression), polyubiquitinated proteins accumulated, and the overall rates of protein degradation were decreased. 26S proteasomes affinity-purified from sciatic nerves of S63del mice were defective in degradation of peptides and a ubiquitinated protein, unlike proteasomes from P0 overexpression, which appeared normal. Nevertheless, cellular levels of 26S proteasomes were increased in both, through the proteolytic-activation of the transcription factor Nrf1, as occurs in response to proteasome inhibitors. In S63del, increased amounts of the deubiquitinating enzymes USP14, UCH37, and USP5 were associated with proteasomes, the first time this has been reported in a human disease model. Inhibitors of USP14 increased the rate of protein degradation in S63del sciatic nerves and unexpectedly increased the phosphorylation of eIF2α by Perk. Thus, proteasome content, composi...Continue Reading

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Citations

Nov 19, 2019·Protein and Peptide Letters·Mohamed A. EldeebFaraz Hussein
Jun 10, 2020·Proceedings of the National Academy of Sciences of the United States of America·Jordan J S VerPlankAlfred L Goldberg
Mar 6, 2019·Cold Spring Harbor Perspectives in Biology·Daniel Finley, Miguel A Prado
Feb 21, 2019·Proceedings of the National Academy of Sciences of the United States of America·Jordan J S VerPlankAlfred L Goldberg
Mar 22, 2019·Frontiers in Cellular and Infection Microbiology·Pedro CurtoJuan J Martinez
Mar 5, 2021·Environmental Science and Pollution Research International·Amit GuptaSandeep Arora
Jun 3, 2021·Biomolecules·Alfred L GoldbergGalen Andrew Collins
Jul 3, 2021·International Journal of Molecular Sciences·Seonghyeon MoonByung-Hoon Lee
Aug 7, 2021·Biomolecules·Iman F Fergani, Luciana R Frick
Aug 13, 2021·Brain : a Journal of Neurology·Jordan J S VerPlankAlfred L Goldberg

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