Loss of SMARCAD1 mitigates tauopathy

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.