Functional Contribution of the Transcription Factor ATF4 to the Pathogenesis of Amyotrophic Lateral Sclerosis
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2013-07-18Metadata
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Matus, Soledad
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Functional Contribution of the Transcription Factor ATF4 to the Pathogenesis of Amyotrophic Lateral Sclerosis
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Abstract
Endoplasmic reticulum (ER) stress represents an early pathological event in amyotrophic lateral sclerosis (ALS). ATF4 is a key
ER stress transcription factor that plays a role in both adaptation to stress and the activation of apoptosis. Here we
investigated the contribution of ATF4 to ALS. ATF4 deficiency reduced the rate of birth of SOD1G86R transgenic mice. The
fraction of ATF42/2-SOD1G85R transgenic mice that were born are more resistant to develop ALS, leading to delayed disease
onset and prolonged life span. ATF4 deficiency completely attenuated the induction of pro-apoptotic genes, including BIM
and CHOP, and also led to quantitative changes in the ER protein homeostasis network. Unexpectedly, ATF4 deficiency
enhanced mutant SOD1 aggregation at the end stage of the disease. Studies in the motoneuron cell line NSC34
demonstrated that knocking down ATF4 enhances mutant SOD1 aggregation possibly due to alteration in the redox status
of the cell. Our results support a functional role of ATF4 in ALS, offering a novel target for disease intervention.
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Millennium Institute
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