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

• DOI: 10.1073/pnas.1917038117
• Publication Date: 2020-05-12T00:25:08Z
• Authors: Josiah J. Herzog; Weijin Xu; Mugdha Deshpande; Reazur Rahman; Hannah Suib; Avital A. Rodal; Michael Rosbash; Suzanne Paradis
• Keywords: 0301 basic medicine; 0303 health sciences; Dendrites; Rats; 3. Good health; DNA-Binding Proteins; 03 medical and health sciences; HEK293 Cells; Gene Expression Regulation; TDP-43 Proteinopathies; Animals; Humans; RNA, Messenger; Cyclic AMP Response Element-Binding Protein; Signal Transduction

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