Premium
Activation of Ets‐2 by oxidative stress induces Bcl‐xL expression and accounts for glial survival in amyotrophic lateral sclerosis
Author(s) -
Lee Junghee,
Kannagi Mari,
Ferrante Robert J.,
Kowall Neil W.,
Ryu Hoon
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/fj.08-121046
Subject(s) - sod1 , amyotrophic lateral sclerosis , oxidative stress , glial fibrillary acidic protein , motor neuron , microglia , biology , microbiology and biotechnology , spinal cord , programmed cell death , bcl xl , astrocyte , transcription factor , chromatin immunoprecipitation , immunology , neuroscience , apoptosis , gene expression , central nervous system , pathology , medicine , endocrinology , promoter , superoxide dismutase , biochemistry , inflammation , gene , immunohistochemistry , disease
Amyotrophic lateral sclerosis (ALS) is an adult‐onset neurodegenerative disease characterized by selective degeneration of motor neurons and glial activation. Cell‐specific transcriptional regulation induced by oxidative stress may contribute to the survival and activation of astrocytes in the face of motor neuron death. In the present study, we demonstrate an age‐dependent increase in Bcl‐xL andEts‐2 immunoreactiv‐ity that correlates with an increase of glial fibrillary acidic protein (GFAP)‐positive cells in the ventral horn of the spinal cord in both ALS transgenic mice [mutant SOD1 (G93A)] and affected humans. Chromatin immu‐noprecipitation (ChIP) analysis verified thatEts‐2 preferentially occupies theEts‐2 binding element in the promoter of Bcl‐xL in primary astrocytes under oxidative stress conditions as well as in G93A spinal cords.Ets‐2 small‐interfering RNA down‐regulated the transcriptional activity of Bcl‐xL. In primary glial cultures, Bcl‐xL overexpression and mutant SOD1 (G93A) both conferred resistance to oxidative stress‐induced cell death. Our findings suggest thatEts‐2 transcription factor activation of Bcl‐xL gene may protect glia from constitutive oxidative stress that is thought to be a key mechanism contributing to the pathogenesis of ALS. This survival pathway may contribute to the glial survival and activation seen in the spinal cord of ALS patients.—Lee, J.,Kannagi, M., Ferrante, R.J., Kowall,N. W., Ryu, H. Activation ofEts‐2 by oxidative stress induces Bcl‐xL expression and accounts for glial survival in amyotrophic lateral sclerosis. FASEB J. 23, 1739–1749 (2009)