Aging drives pathological accumulation of proteins such as tau, causing neurodegenerative dementia disorders like Alzheimer's disease. Previously we showed loss of function mutations in the gene encoding the poly(A) RNA binding protein SUT-2/MSUT2 suppress tau-mediated neurotoxicity in C. elegans neurons, cultured human cells, and mouse brain, while loss of PABPN1 had the opposite effect (Wheeler et al., 2019). Here we found that blocking poly(A) tail extension with cordycepin exacerbates tauopathy in cultured human cells, which is rescued by MSUT2 knockdown. To further investigate the molecular mechanisms of poly(A) RNA-mediated tauopathy suppression, we examined whether genes encoding poly(A) nucleases also modulated tauopathy in a C. elegans tauopathy model. We found that loss of function mutations in C. elegans
ccr-4 and
panl-2 genes enhanced tauopathy phenotypes in tau transgenic C. elegans while loss of
parn-2 partially suppressed tauopathy. In addition, loss of
parn-1 blocked tauopathy suppression by loss of
parn-2. Epistasis analysis showed that
sut-2 loss of function suppressed the tauopathy enhancement caused by loss of
ccr-4 and SUT-2 overexpression exacerbated tauopathy even in the presence of
parn-2 loss of function in tau transgenic C. elegans. Thus
sut-2 modulation of tauopathy is epistatic to
ccr-4 and
parn-2. We found that human deadenylases do not colocalize with human MSUT2 in nuclear speckles; however, expression levels of TOE1, the homolog of
parn-2, correlated with that of MSUT2 in post-mortem Alzheimer's disease patient brains. Alzheimer's disease patients with low TOE1 levels exhibited significantly increased pathological tau deposition and loss of NeuN staining. Taken together, this work suggests suppressing tauopathy cannot be accomplished by simply extending poly(A) tails, but rather a more complex relationship exists between tau,
sut-2/MSUT2 function, and control of poly(A) RNA metabolism, and that
parn-2/TOE1 may be altered in tauopathy in a similar way.