Overexpression of Nfe2l1 increases proteasome activity and delays vision loss in a preclinical model of human blindness

Abstract

Proteasomes are the central proteolytic machines that are critical for breaking down most of the damaged and abnormal proteins in human cells. Although universally applicable drugs are not yet available, the stimulation of proteasomal activity is being analyzed as a proof-of-principle strategy to increase cellular resistance to a broad range of proteotoxic stressors. These approaches have included the stimulation of proteasomes through the overexpression of individual proteasome subunits, phosphorylation, or conformational changes induced by small molecules or peptides. In contrast to these approaches, we evaluated a transcription-driven increase in the total proteasome pool to enhance the proteolytic capacity of degenerating retinal neurons. We show that overexpression of nuclear factor erythroid-2-like 1 (Nfe2l1) transcription factor stimulated proteasome biogenesis and activity, improved the clearance of the ubiquitin-proteasomal reporter, and delayed photoreceptor neuron loss in a preclinical mouse model of human blindness caused by misfolded proteins. The findings highlight Nfe2l1 as an emerging therapeutic target to treat neurodegenerative diseases linked to protein misfolding.

Early recovery of proteasome activity in cells pulse-treated with proteasome inhibitors is independent of DDI2

“…Our findings necessitate reconsidering the role of the DDI2/Nrf1 pathway in basal and inhibitor-induced proteasome expression. Previous studies have also reported that DDI2/Nrf1 contributes to the maintenance of basal levels of proteasomes ( Chen et al, 2022 ; Siva et al, 2020 ; Waku et al, 2020 ) and that Nrf1 is essential for the basal proteasome expression in the brain ( Lee et al, 2011 ), liver ( Lee et al, 2013 ), and retina Wang et al, 2023 ; yet, in our experiments, the effects of DDI2 KO on the basal proteasome activity was not significant ( Figure 1—figure supplement 1 ). These differences may reflect that heavy secretory MM cells, embryonic cells, and certain specific tissues require higher levels of proteasome activity and use the DDI2/Nrf1 pathway to supplement other pathways responsible for proteasome expression ( Motosugi and Murata, 2019 ).…”

Knockout of PA200 improves proteasomal degradation and myelination in a proteotoxic neuropathy

“…The transcription factor Nrf1 mediates the increased expression of 26S proteasomes genes that occurs in response to proteasome inhibitors ( Sha & Goldberg, 2014 ). PSME4 , the gene that encodes PA200, also has a Nrf1 binding site close to its transcriptional start site ( Welk et al, 2016 ), and in mice in which Nrf1 was overexpressed, PSME4 transcription was increased in livers and retina, the only two tissues tested ( Wang et al, 2023 ). This, combined with previous data showing that proteasome subunits and PA200 are upregulated in contexts when the active form of Nrf1 is in the nucleus ( Sha & Goldberg, 2014 ; VerPlank et al, 2018 ), makes it very likely that Nrf1 mediates the upregulation of PSME4 when the proteasome is inhibited, and in S63del mice.…”

Relationships between protein degradation, cellular senescence, and organismal aging

“…Mice with systemic overexpression of Nrf1 exhibited increased proteasome synthesis. When crossed with a mouse model of human blindness, they showed a delayed age-related loss of photoreceptor neurons ( 39 ) .…”