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

Area of Science:

• Neurobiology
• Molecular Biology
• Genetics

Background:

• Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) share TDP-43 protein pathology.
• TDP-43 dysfunction is implicated in neurodegeneration, but the underlying mechanisms are unclear.
• Altered neuronal dendritic morphology is a hallmark of neurological disorders.

Purpose of the Study:

• To identify signaling pathways regulated by TDP-43 that affect neuronal dendritic branching.
• To elucidate the mechanism by which TDP-43 dysfunction leads to neurodegeneration.

Main Methods:

• Utilized TRIBE (targets of RNA-binding proteins identified by editing) to identify TDP-43 RNA targets.
• Assessed CREB activation and transcriptional output in response to TDP-43 manipulation.
• Employed RNA sequencing to analyze mRNA abundance changes.
• Evaluated the impact of restoring CREB signaling on dendritic branching.

Main Results:

• TDP-43 RNA targets are enriched in pathways signaling to the CREB transcription factor.
• TDP-43 dysfunction inhibits CREB activation and its downstream transcriptional activity.
• Restoring CREB signaling rescues TDP-43-induced defects in dendritic branching.
• TDP-43 overexpression and knockdown induce similar changes in mRNA abundance, correlating with morphological defects.

Conclusions:

• TDP-43 dysfunction interferes with dendritic branching via the CREB signaling pathway.
• This study provides a mechanistic link between TDP-43 pathology and neurodegeneration.
• Identified CREB signaling as a potential therapeutic target for ALS, FTD, and related disorders.