Discovery of In Vivo Molecular Pathways Mediating Tau-Induced Sleep and Circadian Disruption
Abstract
During this reporting period, we have discovered 60 RNAi candidates that reproducibly alter sleep and/or circadian rhythmicity when expressed in combination with phosphomimetic Tau (TauE14). We identified these candidates through behavioral screening of nearly 400 Drosophila RNAi strains that target homologs of human genes linked to neurodegeneration through GWAS and systems biology approaches. We have focused on 9 RNAi strains that suppress the behavioral rhythmicity deficits induced by expressing TauE14 in circadian clock neurons. Of these candidates we find that RNAi knockdown of histone deacetylase HDAC1 using two independent RNAi lines suppresses TauE14 rhythmicity defects, validating this gene as a potential mediator of Tau neuropathogenic effects. In parallel to this screen, we have also established a novel model of TauE14 sleep disruption for use in RNAi modifier screening. Our approach validates the use of high-throughput in vivo behavioral screening combined with human genomic studies to identify novel molecular pathways that mediate disease processes in the brain.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2023
- Accession Number
- AD1209096
Entities
People
- Ravi Allada
Organizations
- Northwestern University