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Loss of Nrf1 Function in the Brain Causes Age‐Dependent Neurodegeneration
Author(s) -
Lee Candy ShihChi,
Chan Jefferson J
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.926.6
Subject(s) - nrf1 , neurodegeneration , amyotrophic lateral sclerosis , oxidative stress , biology , knockout mouse , neuroscience , transcription factor , medicine , endocrinology , disease , genetics , gene
Neurodegenerative disease is an important public health issue as the aged population continues to increase. Neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis are caused by gradual loss of neurons. Although molecular mechanisms involved are not fully understood, accumulation of abnormal proteins, mitochondrial defects, and oxidative stress are common in many forms of neurodegenerative diseases. In order to cope with high levels of reactive oxygen species that are normally generated in the brain, antioxidant enzymes are transcriptionally activated in neurons to prevent oxidant damage. Members of CNC‐bZIP (Cap'n'Collar basic leucine zipper) transcription factor family have been implicated in regulating antioxidant gene expression through the antioxidant response element (ARE). Nrf1 is a CNC‐bZIP that is highly expressed in the adult brain, but its role in neurons is not known due to embryonic lethality in Nrf1 germ line mutant mice. Here, we generate and analyze Nrf1 brain conditional knockout mice by using Cre‐Lox system. Mice deficient of Nrf1 in the brain showed age dependent neurobehavioral abnormalities including abnormal leg‐clasping reflex, impaired rotarod performance and hyperactivity. Correspondingly, loss of Nrf1 in the mouse brain leads to age‐dependent brain atrophy as a result of apoptosis. Our studies here demonstrate a novel function of Nrf1 in protecting against neuronal apoptosis. Nrf1 Brain knockout mice may provide a model to study mechanisms of neurodegenerative diseases.