Impairment in the Ubiquitin Proteasome System in hereditary peripheral neuropathies
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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 both neuropathies, increased amounts of the deubiquitinating enzymes USP14 and UCH37 were associated with proteasomes. Inhibitors of USP14 increased the rate of protein degradation in S63del sciatic nerves and unexpectedly decreased protein synthesis in both neuropathies. Thus, proteasome content, composition and activity are altered in these diseases and USP14 inhibitors have therapeutic potential in S63del neuropathy. Proteasome Activator 200 (PA200) was specifically increased in sciatic nerves from S63del mice, leading us to investigate whether this was a compensatory response to the proteasome impairment. The genetic ablation of PA200 in S63del increased the proteasome-specific degradation rate of long-lived proteins in the sciatic nerve. Polyubiquitinated proteins or total proteasome content were not reduced by the ablation of PA200 in S63del, but another proteasome activator, PA28?, associated with the proteasome. The ablation of PA200 improved the morphological and functional deficits associated with the neuropathy. Thus, the increased levels of PA200 were detrimental in S63del neuropathy.