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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2020-05, Vol.117 (21), p.11760-11769
• Main Authors: Herzog, Josiah J., Xu, Weijin, Deshpande, Mugdha, Rahman, Reazur, Suib, Hannah, Rodal, Avital A., Rosbash, Michael, Paradis, Suzanne
• Format: Article
• Language: English
• Subjects: Amyotrophic lateral sclerosis; Animals; Biological Sciences; Cyclic AMP response element-binding protein; Cyclic AMP Response Element-Binding Protein - genetics; Cyclic AMP Response Element-Binding Protein - metabolism; Defects; Dementia disorders; Dendrites - metabolism; Dendrites - pathology; Dendritic branching; Dendritic structure; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Frontotemporal dementia; Gene expression; Gene Expression Regulation - genetics; Gene sequencing; HEK293 Cells; Humans; Metabolism; Morphology; Neurodegeneration; Neurodegenerative diseases; Neurological diseases; Neurons; Proteins; Rats; Ribonucleic acid; RNA; RNA, Messenger - metabolism; RNA-binding protein; Signal transduction; Signal Transduction - genetics; Signal Transduction - physiology; Signaling; Target recognition; TDP-43 Proteinopathies; Transcription activation
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1917038117

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.