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

Proc Natl Acad Sci U S A. 2020 May 26;117(21):11760-11769. doi: 10.1073/pnas.1917038117. Epub 2020 May 11.


Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two related neurodegenerative diseases that present with similar TDP-43 pathology in patient tissue. TDP-43 is an RNA-binding protein which forms aggregates in neurons of ALS and FTD patients as well as in a subset of patients diagnosed with other neurodegenerative diseases. Despite our understanding that TDP-43 is essential for many aspects of RNA metabolism, it remains obscure how TDP-43 dysfunction contributes to neurodegeneration. Interestingly, altered neuronal dendritic morphology is a common theme among several neurological disorders and is thought to precede neurodegeneration. We previously found that both TDP-43 overexpression (OE) and knockdown (KD) result in reduced dendritic branching of cortical neurons. In this study, we used TRIBE (targets of RNA-binding proteins identified by editing) as an approach to identify signaling pathways that regulate dendritic branching downstream of TDP-43. We found that TDP-43 RNA targets are enriched for pathways that signal to the CREB transcription factor. We further found that TDP-43 dysfunction inhibits CREB activation and CREB transcriptional output, and restoring CREB signaling rescues defects in dendritic branching. Finally, we demonstrate, using RNA sequencing, that TDP-43 OE and KD cause similar changes in the abundance of specific messenger RNAs, consistent with their ability to produce similar morphological defects. Our data therefore provide a mechanism by which TDP-43 dysfunction interferes with dendritic branching, and may define pathways for therapeutic intervention in neurodegenerative diseases.

Keywords: CREB; TDP-43; TRIBE.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cyclic AMP Response Element-Binding Protein* / genetics
  • Cyclic AMP Response Element-Binding Protein* / metabolism
  • DNA-Binding Proteins* / genetics
  • DNA-Binding Proteins* / metabolism
  • Dendrites* / metabolism
  • Dendrites* / pathology
  • Gene Expression Regulation / genetics*
  • HEK293 Cells
  • Humans
  • RNA, Messenger / metabolism
  • Rats
  • Signal Transduction* / genetics
  • Signal Transduction* / physiology
  • TDP-43 Proteinopathies


  • CREB1 protein, human
  • Cyclic AMP Response Element-Binding Protein
  • DNA-Binding Proteins
  • RNA, Messenger
  • TARDBP protein, human