NRF1 is Neuroprotective via Proteasomal Function – Fight Aging!

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Cells maintain themselves against damage and stress via a range of maintenance processes. These include autophagy, in which proteins and structures are transported to the lysosome to be broken down by enzymes, and the ubiquitin-proteasome system, in which specific proteins are dismantled in the proteasome, among others. It is well demonstrated that upregulation of these processes improves resistance to cell stress, and can also improve long-term health, reducing risk of age-related disease and slowing progression of those conditions. Upregulation of autophagy, for example, is a feature of many interventions that modestly slow the progression of degenerative aging. Some approaches to improve proteasomal function have also been shown to slow aging and extend life in short-lived species. Thus a broad range of research is focused on increasing the efficiency or effectiveness of these processes.


In today’s open access paper, researchers discuss upregulation of NRF1, also known as NFE2L1, as a way to improve proteasomal function. The specific focus is neurodegeneration rather than aging more generally, but it is still the case that greater resistance to the consequences of cell stress can preserve function in the face of many distinct and complex damaging processes. While the research community expends a great deal of time and effort on the question of how to improve the operation of systems of cell maintenance, it remains the case that few well developed therapies have shown any improvement over exercise in this respect. Large gains seem elusive, particularly as effect sizes appear to diminish with increased species life span. This perhaps suggests that many of the possible optimizations are already operating in long-lived species.


NFE2L1/Nrf1 serves as a potential therapeutical target for neurodegenerative diseases



Nuclear factor-erythroid 2 (NFE2)-related factor 1 (Nrf1, encoded by NFE2L1) acts as a transcription factor involved in multiple essential life processes, e.g., redox signaling, cellular metabolism, and proteasomal regulation. Of note, NFE2L1 binds to the promoter regions of its target genes through the antioxidant response elements (AREs), crucially to drive transactivation of those stress-responsive and cytoprotective genes, which are also present in the promoters of genes encoding proteasomal subunits. Further studies revealed that NFE2L1 regulates multiple antioxidant genes, such as HMOX1, SOD1, or GCLC; it has also been verified as a master regulator of the ubiquitin-proteasome system (UPS) by controlling the transcriptional expression of almost all proteasome subunits and relevant co-factors.



Multiple neuroprotective interventions, as aforementioned, rely mainly on increasing NFE2L1 activity in neurons, which enhances the cell survival ability to defend against various stressors. NFE2L1 is essential for the proper functioning of proteasomes, and its lack results in an aberrant accumulation of ubiquitinated proteins through the nervous system. Notably, the knockout of the NFE2L1 gene in animal models brings about severe pathology resembling human neurodegenerative diseases. In the postmortem analyses, reduced NFE2L1 levels were found in the substantia nigra region of patients with Parkinson’s disease and in the hippocampus of patients with Alzheimer’s disease. This presents a strong case of NFE2L1 deficiency involved in the pathogenesis of neurodegenerative diseases.



Therefore, it is plausible that NFE2L1 has significant potential in translational medicine to serve as a therapeutic target for these neurodegenerative diseases. Nevertheless, since NFE2L1 is widely expressed throughout a given organism’s whole body, a neuron-specific activation of this transcription factor would be more beneficial to minimize off-target effects.

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