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

• Published in: Biochimica et biophysica acta. Molecular basis of disease 2025-01, Vol.1871 (1), p.167562, Article 167562
• Main Authors: Clarke, Joseph-Patrick W.E., Messmer, Miranda L., Pilon, Jacob, Reding, Jenna, Thibault, Patricia A., Salapa, Hannah E., Levin, Michael C.
• Format: Article
• Language: English
• Subjects: Acetamides; Animals; Cell stress inhibition; Cyclohexylamines; Heterogeneous Nuclear Ribonucleoprotein A1 - genetics; Heterogeneous Nuclear Ribonucleoprotein A1 - metabolism; HNRNPA1; Humans; Mice; Multiple Sclerosis - metabolism; Multiple Sclerosis - pathology; Neurite loss; Neurites - metabolism; Neurites - pathology; Neurons - metabolism; Neurons - pathology; Optogenetics; Protein clustering; Protein translation; Stress, Physiological
• ISSN: 0925-4439; 1879-260X; 1879-260X
• DOI: 10.1016/j.bbadis.2024.167562

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 (integrated stress response inhibitor) 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. •hnRNP A1 clustering activates the ISR and results in a neurodegenerative phenotype.•Small molecule inhibition of the ISR attenuated the neurodegenerative phenotype, without affecting hnRNP A1 clustering.•There is a strong association between hnRNP A1 clustering and ISR activation in neurons from MS brains.•Overall, hnRNP A1 dysfunction promotes neurodegeneration by activation of the ISR in vitro and in vivo.•Inhibiting ISR activation is a novel therapeutic target to reduce neurodegeneration and subsequent disability in MS.