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TDP-43 misexpression causes defects in dendritic growth
Josiah J Herzog1, Mugdha Deshpande1, Leah Shapiro1
1Department of Biology, Volen Center for Complex Systems, and National Center for Behavioral Genomics, Brandeis University, Waltham, Massachusetts, 02454, USA.
Scientific Reports
|November 17, 2017
Summary
Dysfunction of TAR DNA binding protein-43 (TDP-43) impairs neuronal dendritic growth in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). This study reveals TDP-43’s RNA-binding role in neuronal development, offering therapeutic targets.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) share genetic links and neuropathology involving the RNA-binding protein TDP-43.
- TDP-43 dysfunction is implicated in neurodegeneration, but its precise cellular mechanisms, particularly concerning neuronal structure, are not fully understood.
- Aberrant dendritic morphology is observed in ALS/FTD, yet its direct link to TDP-43 dysfunction remains largely unexplored.
Purpose of the Study:
- To investigate the cellular effects of TDP-43 dysfunction on neuronal structure, specifically dendritic morphology.
- To explore the role of TDP-43 in regulating dendritic arborization in hippocampal and cortical neurons.
- To establish a model system for identifying therapeutic targets for ALS and FTD.
Main Methods:
- Utilized a primary rodent neuronal culture model.
- Manipulated TDP-43 expression levels in neurons.
- Assessed effects on dendritic branching, outgrowth, and cell viability.
- Investigated the dependency of morphological changes on TDP-43's RNA-binding ability.
Main Results:
- TDP-43 manipulation led to significant defects in dendritic branching and outgrowth.
- These dendritic morphology changes occurred without immediate impact on neuronal cell viability.
- The observed effects on dendritic structure were dependent on the RNA-binding capacity of TDP-43.
Conclusions:
- TDP-43 plays a crucial role in regulating neuronal dendritic arborization.
- The RNA-binding function of TDP-43 is essential for maintaining normal dendritic morphology.
- This research provides a valuable model for uncovering downstream pathways of TDP-43 and developing novel therapeutic strategies for ALS and FTD.
