Transcriptomic Analysis of Zebrafish TDP-43 Transgenic Lines

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting motor neurons.
• Mutations in the TARDBP gene, encoding TDP-43 protein, are strongly linked to ALS.
• TDP-43 is a key component of neuronal inclusions in ALS, and mutations may cause toxic gain-of-function.

Purpose of the Study:

• To generate and characterize transgenic zebrafish models expressing wild-type and mutant human TDP-43.
• To investigate the effects of mutant TDP-43 on motor neuron function and behavior in vivo.
• To identify transcriptomic alterations associated with mutant TDP-43 expression.

Main Methods:

• Generation of inducible transgenic zebrafish lines expressing wild-type or G348C mutant human TDP-43.
• Assessment of locomotor activity and motor neuron axon morphology in zebrafish embryos.
• RNA sequencing to analyze global gene expression changes in response to mutant TDP-43.

Main Results:

• Expression of mutant TDP-43, but not wild-type, led to reduced locomotor activity and moderate axonopathy in zebrafish motor neurons.
• RNA sequencing identified 159 differentially expressed genes (67 upregulated, 92 downregulated) in response to mutant TDP-43.
• The observed transcriptomic changes align with findings from mouse models of ALS.

Conclusions:

• Transgenic zebrafish expressing mutant TDP-43 effectively recapitulate key aspects of TDP-43 proteinopathy in ALS.
• These zebrafish models provide a valuable platform for studying the molecular mechanisms of ALS.
• The identified transcriptomic changes offer insights into the cellular pathways affected in TDP-43-related neurodegeneration.