Dysfunctional RNA binding protein induced neurodegeneration is attenuated by inhibition of the integrated stress response

This is the authors' abstract. We don't add key points for this paper.

Dysfunction of the RNA binding protein heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) contributes to neurodegeneration, the primary cause of permanent disability in multiple sclerosis (MS). To better understand the role of hnRNP A1 dysfunction in the pathogenesis of neurodegeneration, we utilized optogenetics-driven hnRNP A1 clustering to model its dysfunction in neuron-like differentiated Neuro-2A cells. hnRNP A1 clustering activates the integrated stress response (ISR) and results in a neurodegenerative phenotype marked by decreased neuronal protein translation and neurite loss. Small molecule inhibition of the ISR with either PERKi (GSK2606414) or ISRIB ( i ntegrated s tress r esponse i nhi b itor) attenuated both the decrease in neuronal translation and neurite loss, without affecting hnRNP A1 clustering. We then confirmed a strong association between hnRNP A1 clustering and ISR activation in neurons from MS brains. These data illustrate that hnRNP A1 dysfunction promotes neurodegeneration by activation of the ISR in vitro and in vivo , thus revealing a novel therapeutic target to reduce neurodegeneration and subsequent disability in MS. • Office of the Saskatchewan Multiple Sclerosis Clinical Research Chair, University of Saskatchewan, Saskatoon, SK, Canada, S7K-0M7 • Cameco MS Neuroscience Research Centre, College of Medicine, University of Saskatchewan, Saskatoon, SK S7K 0M7 Canada • Department of Medicine, Neurology Division, University of Saskatchewan, Saskatoon, SK, Canada, S7N-5E5 • Department of Health Sciences, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada, S7N-5E5 • Department of Anatomy, Physiology and Pharmacology, University of Saskatchewan, Saskatoon, SK, Canada, S7N-5E5