Loss of SMARCAD1 Mitigates Tauopathy

Tauopathies are neurodegenerative diseases characterized by the accumulation of misfolded tau protein and include Alzheimer's disease (AD) and related dementia disorders. Identifying new strategies to treat tauopathy remains an important gap in the field. 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. 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. Immunohistochemistry in human postmortem AD brain tissue showed SMARCAD1 depletion in a subset of cases that also exhibit depletion of MSUT2. Loss of smrd-1/SMARCAD1 rescues tau-mediated neurodegeneration via a tau mRNA lowering mechanism accompanied by changes in chromatin conformation.