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Distinct Poly(A) nucleases have differential impact on sut-2 dependent tauopathy phenotypes

التفاصيل البيبلوغرافية
العنوان: Distinct Poly(A) nucleases have differential impact on sut-2 dependent tauopathy phenotypes
المؤلفون: Pamela J. McMillan, Aleen D. Saxton, Mark A. Behlke, Timothy J. Strovas, Rebecca L. Kow, Brian C. Kraemer, Ashley M. Jacobi, C. Dirk Keene, Caitlin S. Latimer
المصدر: Neurobiology of disease
Neurobiology of Disease, Vol 147, Iss, Pp 105148-(2021)
سنة النشر: 2020
مصطلحات موضوعية: 0301 basic medicine, Neurofibrillary tangles, PARN, Transgene, RNA-binding protein, Biology, Poly(A)-Binding Proteins, Article, lcsh:RC321-571, Animals, Genetically Modified, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, medicine, Animals, Humans, SUTSUT-2, Neurodegeneration, Caenorhabditis elegans, Caenorhabditis elegans Proteins, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Loss function, Gene knockdown, Neurotoxicity, Brain, Nuclear Proteins, TOE1, medicine.disease, Cell biology, 030104 developmental biology, Phenotype, Neurology, Tauopathies, Exoribonucleases, MSUT2, biology.protein, Tauopathy, CCR4, NeuN, Tau, Poly(A) deadenylases, 030217 neurology & neurosurgery
الوصف: 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.
تدمد: 1095-953X
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::231b90f0f8921e9852fbc349ef8dbabd
https://pubmed.ncbi.nlm.nih.gov/33184027
حقوق: OPEN
رقم الأكسشن: edsair.doi.dedup.....231b90f0f8921e9852fbc349ef8dbabd
قاعدة البيانات: OpenAIRE
الوصف
تدمد:1095953X