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Autophagy. 2016 Oct 2;12(10):1902-1916. Epub 2016 Jul 18.

Transcription factor NFE2L2/NRF2 is a regulator of macroautophagy genes.

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a Instituto de Investigaciones Biomédicas "Alberto Sols" UAM-CSIC, Instituto de Investigación Sanitaria La Paz (IdiPaz) and Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid , Madrid , Spain.
b Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII , Madrid , Spain.
c Present address: School of Biochemistry, University of Bristol, Medical Sciences Building, University Walk , Bristol , UK.
d Neurodegeneration Group, Department of Cellular, Molecular and Developmental Neurobiology, Instituto Cajal, Consejo Superior de Investigaciones Científicas , Madrid , Spain.
e Experimental Genetics Group-LEGTEGG, Department of Human Genetics, KU Leuven , Leuven , Belgium.
f Department of Neuropathology and Tissue Bank , Unidad de Investigación Proyecto Alzheimer, Fundación CIEN, Instituto de Salud Carlos III , Madrid , Spain.
g Department of Medical Biochemistry , Tohoku University Graduate School of Medicine , Aoba-ku , Sendai , Japan.


Autophagy is a highly coordinated process that is controlled at several levels including transcriptional regulation. Here, we identify the transcription factor NFE2L2/NRF2 (nuclear factor, erythroid 2 like 2) as a regulator of autophagy gene expression and its relevance in a mouse model of Alzheimer disease (AD) that reproduces impaired APP (amyloid β precursor protein) and human (Hs)MAPT/TAU processing, clearance and aggregation. We screened the chromatin immunoprecipitation database ENCODE for 2 proteins, MAFK and BACH1, that bind the NFE2L2-regulated enhancer antioxidant response element (ARE). Using a script generated from the JASPAR's consensus ARE sequence, we identified 27 putative AREs in 16 autophagy-related genes. Twelve of these sequences were validated as NFE2L2 regulated AREs in 9 autophagy genes by additional ChIP assays and quantitative RT-PCR on human and mouse cells after NFE2L2 activation with sulforaphane. Mouse embryo fibroblasts of nfe2l2-knockout mice exhibited reduced expression of autophagy genes, which was rescued by an NFE2L2 expressing lentivirus, and impaired autophagy flux when exposed to hydrogen peroxide. NFE2L2-deficient mice co-expressing HsAPPV717I and HsMAPTP301L, exhibited more intracellular aggregates of these proteins and reduced neuronal levels of SQSTM1/p62, CALCOCO2/NDP52, ULK1, ATG5 and GABARAPL1. Also, colocalization of HsAPPV717I and HsMAPTP301L with the NFE2L2-regulated autophagy marker SQSTM1/p62 was reduced in the absence of NFE2L2. In AD patients, neurons expressing high levels of APP or MAPT also expressed SQSTM1/p62 and nuclear NFE2L2, suggesting their attempt to degrade intraneuronal aggregates through autophagy. This study shows that NFE2L2 modulates autophagy gene expression and suggests a new strategy to combat proteinopathies.


Alzheimer disease; Tau; amyloid precursor protein; neurodegenerative diseases; neuroprotection; oxidative stress; proteostasis

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