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Significance TDP-43 is an RNA-binding protein closely associated with neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We have previously shown that TDP-43 dysfunction leads to reduced dendritic complexity. In this study, we apply the recently developed genetic approach TRIBE (targets of RNA-binding proteins identified by editing) to identify the RNAs that are bound by TDP-43 in neurons. Of the many TDP-43 target RNAs identified, we observed that mRNAs encoding proteins related to the CREB signaling pathway are enriched. Next, we were able to rescue the dendritic complexity defect caused by TDP-43 dysfunction by restoring CREB signaling. Our study may provide pathways for therapeutic intervention in TDP-43−associated neurodegenerative diseases.

TDP-43 dysfunction restricts dendritic complexity by inhibiting CREB activation and altering gene expression