RRC ID 76636
Author Wang Y, Snell A, Dyka FM, Colvin ER, Ildefonso C, Ash JD, Lobanova ES.
Title Overexpression of Nfe2l1 increases proteasome activity and delays vision loss in a preclinical model of human blindness.
Journal Sci Adv
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.
Volume 9(28)
Pages eadd5479
Published 2023-7-14
DOI 10.1126/sciadv.add5479
PMID 37450596
PMC PMC10348684
MeSH Animals Blindness Humans Mice Proteasome Endopeptidase Complex* / metabolism Proteolysis Transcription Factors* / metabolism Ubiquitin / metabolism
IF 13.117
Mice RBRC10149