MYCOLab Ai Logo - gold and army green

Transcriptional programs mediating neuronal toxicity and altered glial–neuronal signaling in a Drosophila knock-in tauopathy model

Summary

Researchers created a fruit fly model of frontotemporal dementia by editing the tau gene to match a human disease mutation. Using advanced genetic sequencing technology, they analyzed how this mutation affects brain cells, discovering that it disrupts communication between nerve cells and support cells called glia. The study reveals multiple pathways that could be targeted with future treatments to combat this devastating brain disease.

Background

Missense mutations in the TAU gene cause autosomal dominant frontotemporal dementia. While transgenic models of tauopathy have been useful, they do not faithfully replicate the genetic context of human disease. This study uses CRISPR-Cas9 to create a knock-in model with the P251L mutation orthologous to the human P301L mutation.

Objective

To model frontotemporal dementia caused by the TAU P301L mutation using CRISPR-mediated gene editing in Drosophila and to comprehensively characterize molecular pathways underlying neuronal toxicity and glial-neuronal communication using single-cell RNA sequencing.

Results

Tau P251L knock-in flies displayed age-dependent neurodegeneration, metabolic defects, DNA damage accumulation, and abnormal cell-cycle reentry. Single-cell RNA sequencing identified pervasive dysregulation of gene expression in neurons and glia, with altered cell-cell communication pathways including synaptic plasticity, JAK-STAT, hippo, and TNF-α signaling.

Conclusion

The Tau P251L knock-in model faithfully recapitulates human tauopathy features in appropriate genetic context. Comprehensive transcriptional analysis reveals complex neuronal and non-cell-autonomous glial contributions to disease pathogenesis, highlighting multiple signaling pathways as potential therapeutic targets.
  • Published in:Genome Research,
  • Study Type:Experimental Research, Genomic Study,
  • Source: PMID: 38599684, DOI: 10.1101/gr.278576.123
Scroll to Top