Distinct Poly(A) nucleases have differential impact on sut-2 dependent tauopathy phenotypes.
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. elega...
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| Format: | Article |
| Language: | English |
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Elsevier
2021-01-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S096999612030423X |
| _version_ | 1818651539645923328 |
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| author | Rebecca L. Kow Timothy J. Strovas Pamela J. McMillan Ashley M. Jacobi Mark A. Behlke Aleen D. Saxton Caitlin S. Latimer C. Dirk Keene Brian C. Kraemer |
| author_facet | Rebecca L. Kow Timothy J. Strovas Pamela J. McMillan Ashley M. Jacobi Mark A. Behlke Aleen D. Saxton Caitlin S. Latimer C. Dirk Keene Brian C. Kraemer |
| author_sort | Rebecca L. Kow |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-17T02:07:43Z |
| format | Article |
| id | doaj.art-a306260c5f1f44a8881453e339558866 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-17T02:07:43Z |
| publishDate | 2021-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-a306260c5f1f44a8881453e3395588662022-12-21T22:07:39ZengElsevierNeurobiology of Disease1095-953X2021-01-01147105148Distinct Poly(A) nucleases have differential impact on sut-2 dependent tauopathy phenotypes.Rebecca L. Kow0Timothy J. Strovas1Pamela J. McMillan2Ashley M. Jacobi3Mark A. Behlke4Aleen D. Saxton5Caitlin S. Latimer6C. Dirk Keene7Brian C. Kraemer8Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health, Care System, Seattle, WA 98108, USA; Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, WA 98104, USAGeriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health, Care System, Seattle, WA 98108, USADivision of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, WA 98104, USA; Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195, USAIntegrated DNA Technologies, Coralville, IA 52241, USAIntegrated DNA Technologies, Coralville, IA 52241, USAGeriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health, Care System, Seattle, WA 98108, USADepartment of Pathology, University of Washington, Seattle, WA 98195, USADepartment of Pathology, University of Washington, Seattle, WA 98195, USAGeriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health, Care System, Seattle, WA 98108, USA; Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, WA 98104, USA; Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195, USA; Department of Pathology, University of Washington, Seattle, WA 98195, USA; Corresponding author at: Seattle Veterans Affairs Puget Sound Health Care System, S182, 1660 South Columbian Way, Seattle, WA 98108, USA.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.http://www.sciencedirect.com/science/article/pii/S096999612030423XTauSUTSUT-2MSUT2Poly(A) deadenylasesTOE1Neurofibrillary tangles |
| spellingShingle | Rebecca L. Kow Timothy J. Strovas Pamela J. McMillan Ashley M. Jacobi Mark A. Behlke Aleen D. Saxton Caitlin S. Latimer C. Dirk Keene Brian C. Kraemer Distinct Poly(A) nucleases have differential impact on sut-2 dependent tauopathy phenotypes. Neurobiology of Disease Tau SUTSUT-2 MSUT2 Poly(A) deadenylases TOE1 Neurofibrillary tangles |
| title | Distinct Poly(A) nucleases have differential impact on sut-2 dependent tauopathy phenotypes. |
| title_full | Distinct Poly(A) nucleases have differential impact on sut-2 dependent tauopathy phenotypes. |
| title_fullStr | Distinct Poly(A) nucleases have differential impact on sut-2 dependent tauopathy phenotypes. |
| title_full_unstemmed | Distinct Poly(A) nucleases have differential impact on sut-2 dependent tauopathy phenotypes. |
| title_short | Distinct Poly(A) nucleases have differential impact on sut-2 dependent tauopathy phenotypes. |
| title_sort | distinct poly a nucleases have differential impact on sut 2 dependent tauopathy phenotypes |
| topic | Tau SUTSUT-2 MSUT2 Poly(A) deadenylases TOE1 Neurofibrillary tangles |
| url | http://www.sciencedirect.com/science/article/pii/S096999612030423X |
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