Rbm45 Modulates The Antioxidant Response In Amyotrophic Lateral Sclerosis Through Interactions With Keap1
Department
neurobiology
Document Type
Article
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective loss of motor neurons. Various factors contribute to the disease, including RNA binding protein dysregulation and oxidative stress, but their exact role in pathogenic mechanisms remains unclear. We have recently linked another RNA binding protein, RBM45, to ALS via increased levels of protein in the cerebrospinal fluid of ALS patients and its localization to cytoplasmic inclusions in ALS motor neurons. Here we show RBM45 nuclear exit in ALS spinal cord motor neurons compared to controls, a phenotype recapitulated in vitro in motor neurons treated with oxidative stressors. We find that RBM45 binds and stabilizes KEAP1, the inhibitor of the antioxidant response transcription factor NRF2. ALS lumbar spinal cord lysates similarly show increased cytoplasmic binding of KEAP1 and RBM45. Binding of RBM45 to KEAP1 impedes the protective antioxidant response, thus contributing to oxidative stress-induced cellular toxicity. Our findings thus describe a novel link between a mislocalized RNA binding protein implicated in ALS (RBM45) and dysregulation of the neuroprotective antioxidant response seen in the disease.
Publication Date
1-1-2015
Publication Title
Molecular and Cellular Biology
ISSN
02707306
Volume
35
Issue
14
First Page
2385
Last Page
2399
Digital Object Identifier (DOI)
10.1128/MCB.00087-15
Recommended Citation
Bakkar, Nadine; Kousari, Arianna; Kovalik, Tina; Li, Yang; and Bowser, Robert, "Rbm45 Modulates The Antioxidant Response In Amyotrophic Lateral Sclerosis Through Interactions With Keap1" (2015). Translational Neuroscience. 4.
https://scholar.barrowneuro.org/neurobiology/4