Neuroprotective Role of the Basic Leucine Zipper Transcription Factor NFIL3 in Models of Amyotrophic Lateral Sclerosis

Background: ALS is a motor neuron disease characterized by the loss of axons and neurons. Results: NFIL3 protects neurons in cellular and animal models of ALS. Conclusion: NFIL3 is a neuroprotective molecule intrinsic to neurons. Significance: NFIL3 is a potential therapeutic target for the treatment of ALS and related neurodegenerative diseases. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the loss of motor neurons. Here we show that the basic leucine zipper transcription factor NFIL3 (also called E4BP4) confers neuroprotection in models of ALS. NFIL3 is up-regulated in primary neurons challenged with neurotoxic insults and in a mouse model of ALS. Overexpression of NFIL3 attenuates excitotoxic neuronal damage and protects neurons against neurodegeneration in a cell-based ALS model. Conversely, reduction of NFIL3 exacerbates neuronal demise in adverse conditions. Transgenic neuronal expression of NFIL3 in ALS mice delays disease onset and attenuates motor axon and neuron degeneration. These results suggest that NFIL3 plays a neuroprotective role in neurons and constitutes a potential therapeutic target for neurodegeneration.