GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE297nnn/GSE297216/primaryOK200TranscriptomicsCaenorhabditis elegansExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE297216GEOGSEfalseLoss of SMARCAD1 mitigates tauopathyBackground Tauopathies are neurodegenerative diseases characterized by the accumulation of misfolded tau protein in Alzheimer’s disease (AD) and related dementia disorders. Identifying new strategies to treat tauopathy remains an important gap in the field. Methods Using forward and reverse genetic approaches in C. elegans, we identified smrd-1 the C. elegans homolog of SMARCAD1 as a potent modifier of tauopathy phenotypes in a transgenic model of tauopathy. Results Loss of smrd-1 function rescues tauopathy associated neuronal dysfunction and neurodegeneration in C. elegans models of tauopathy. Loss or reduction of smrd-1/SMARCAD1 decreases phosphorylated and total tau protein levels by reducing tau mRNA transcripts in C. elegans and mammalian HEK-tau cells. Loss of smrd-1 rescues tau-driven abnormal H3K9me3 chromatin methylation. We identified mir-235 potentially acting downstream of smrd-1 in conferring tauopathy rescue. Immunohistochemistry in human postmortem AD brain tissue found SMARCAD1 depletion in a subset of cases that also exhibit depletion of MSUT2. Conclusion Loss of smrd-1/SMARCAD1 rescues tau mediated neurodegeneration via a tau mRNA lowering mechanism involving changes in chromatin conformation.2026/06/11GSE297216GSM8986437GSM8986438GSM8986439GSM8986432GSM8986433GSM8986434GSM8986435GSM898643634620297216Caenorhabditis elegans[42204442]