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Possible roles of the transcription factor Nrf1 (NFE2L1) in neural homeostasis by regulating the gene expression of deubiquitinating enzymes

Author:
Taniguchi, Hiroaki, Okamuro, Shota, Koji, Misaki, Waku, Tsuyoshi, Kubo, Kaori, Hatanaka, Atsushi, Sun, Yimeng, Chowdhury, A.M. Masudul Azad, Fukamizu, Akiyoshi, Kobayashi, Akira
Source:
Biochemical and biophysical research communications 2017 v.484 pp. 176-183
ISSN:
0006-291X
Subject:
cerebellum, cerebral cortex, databases, gene expression, genes, homeostasis, mice, microarray technology, motor neurons, neurodegenerative diseases, proteasome endopeptidase complex, proteolysis, stem cells, transcription factors
Abstract:
The transcription factor Nrf1 (NFE2L1) maintains protein homeostasis (proteostasis) by regulating the gene expression of proteasome subunits in response to proteasome inhibition. The deletion of the Nrf1 gene in neural stem/progenitor cells causes severe neurodegeneration due to the accumulation of ubiquitinated proteins in Purkinje cells and motor neurons (Nrf1 NKO mice). However, the molecular mechanisms governing this neurodegenerative process remain unclear. We demonstrate herein that the loss of Nrf1 leads to the reduced gene expression of the deubiquitinating enzymes (DUBs) but not proteasome subunits in Nrf1 NKO mice between P7 and P18. First, we show that K48-linked polyubiquitinated proteins accumulate in Nrf1-deficient Purkinje cells and cerebral cortex neurons. Nevertheless, loss of Nrf1 does not alter the expression and proteolytic activity of proteasome. A significantly reduced expression of deubiquitinating enzymes was also demonstrated in Nrf1-deficient cerebellar tissue using microarray analysis. The genome database further reveals species-conserved ARE, a Nrf1 recognition element, in the regulatory region of certain DUB genes. Furthermore, we show that Nrf1 can activate Usp9x gene expression related to neurodegeneration. Altogether these findings suggest that neurodegeneration in Nrf1 NKO mice may stem from the dysfunction of the ubiquitin-mediated regulation of neuronal proteins.
Agid:
5609687