Drosophila Ref1/ALYREF regulates transcription and toxicity associated with ALS/FTD disease etiologies
Abstract RNA-binding proteins (RBPs) are associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but the underlying disease mechanisms remain unclear. In an unbiased screen in Drosophila for RBPs that genetically interact with TDP-43, we found that downregulation of th...
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| Format: | Article |
| Language: | English |
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BMC
2019-04-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40478-019-0710-x |
| _version_ | 1818307427253092352 |
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| author | Amit Berson Lindsey D. Goodman Ashley N. Sartoris Charlton G. Otte James A. Aykit Virginia M.-Y. Lee John Q. Trojanowski Nancy M. Bonini |
| author_facet | Amit Berson Lindsey D. Goodman Ashley N. Sartoris Charlton G. Otte James A. Aykit Virginia M.-Y. Lee John Q. Trojanowski Nancy M. Bonini |
| author_sort | Amit Berson |
| collection | DOAJ |
| description | Abstract RNA-binding proteins (RBPs) are associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but the underlying disease mechanisms remain unclear. In an unbiased screen in Drosophila for RBPs that genetically interact with TDP-43, we found that downregulation of the mRNA export factor Ref1 (fly orthologue to human ALYREF) mitigated TDP-43 induced toxicity. Further, Ref1 depletion also reduced toxicity caused by expression of the C9orf72 GGGGCC repeat expansion. Ref1 knockdown lowered the mRNA levels for these related disease genes and reduced the encoded proteins with no effect on a wild-type Tau disease transgene or a control transgene. Interestingly, expression of TDP-43 or the GGGGCC repeat expansion increased endogenous Ref1 mRNA levels in the fly brain. Further, the human orthologue ALYREF was upregulated by immunohistochemistry in ALS motor neurons, with the strongest upregulation occurring in ALS cases harboring the GGGGCC expansion in C9orf72. These data support ALYREF as a contributor to ALS/FTD and highlight its downregulation as a potential therapeutic target that may affect co-existing disease etiologies. |
| first_indexed | 2024-12-13T06:58:12Z |
| format | Article |
| id | doaj.art-a8dbde8e1b534815af67340eabe6e702 |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-12-13T06:58:12Z |
| publishDate | 2019-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-a8dbde8e1b534815af67340eabe6e7022022-12-21T23:56:00ZengBMCActa Neuropathologica Communications2051-59602019-04-017111010.1186/s40478-019-0710-xDrosophila Ref1/ALYREF regulates transcription and toxicity associated with ALS/FTD disease etiologiesAmit Berson0Lindsey D. Goodman1Ashley N. Sartoris2Charlton G. Otte3James A. Aykit4Virginia M.-Y. Lee5John Q. Trojanowski6Nancy M. Bonini7Department of Biology, University of PennsylvaniaNeuroscience Graduate Group, Perelman School of Medicine, University of PennsylvaniaDepartment of Biology, University of PennsylvaniaDepartment of Biology, University of PennsylvaniaDepartment of Biology, University of PennsylvaniaDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of PennsylvaniaDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of PennsylvaniaDepartment of Biology, University of PennsylvaniaAbstract RNA-binding proteins (RBPs) are associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but the underlying disease mechanisms remain unclear. In an unbiased screen in Drosophila for RBPs that genetically interact with TDP-43, we found that downregulation of the mRNA export factor Ref1 (fly orthologue to human ALYREF) mitigated TDP-43 induced toxicity. Further, Ref1 depletion also reduced toxicity caused by expression of the C9orf72 GGGGCC repeat expansion. Ref1 knockdown lowered the mRNA levels for these related disease genes and reduced the encoded proteins with no effect on a wild-type Tau disease transgene or a control transgene. Interestingly, expression of TDP-43 or the GGGGCC repeat expansion increased endogenous Ref1 mRNA levels in the fly brain. Further, the human orthologue ALYREF was upregulated by immunohistochemistry in ALS motor neurons, with the strongest upregulation occurring in ALS cases harboring the GGGGCC expansion in C9orf72. These data support ALYREF as a contributor to ALS/FTD and highlight its downregulation as a potential therapeutic target that may affect co-existing disease etiologies.http://link.springer.com/article/10.1186/s40478-019-0710-xALYREFRef1DrosophilaAmyotrophic lateral sclerosis (ALS) (Lou Gehrig disease)Ataxin-2C9orf72 |
| spellingShingle | Amit Berson Lindsey D. Goodman Ashley N. Sartoris Charlton G. Otte James A. Aykit Virginia M.-Y. Lee John Q. Trojanowski Nancy M. Bonini Drosophila Ref1/ALYREF regulates transcription and toxicity associated with ALS/FTD disease etiologies Acta Neuropathologica Communications ALYREF Ref1 Drosophila Amyotrophic lateral sclerosis (ALS) (Lou Gehrig disease) Ataxin-2 C9orf72 |
| title | Drosophila Ref1/ALYREF regulates transcription and toxicity associated with ALS/FTD disease etiologies |
| title_full | Drosophila Ref1/ALYREF regulates transcription and toxicity associated with ALS/FTD disease etiologies |
| title_fullStr | Drosophila Ref1/ALYREF regulates transcription and toxicity associated with ALS/FTD disease etiologies |
| title_full_unstemmed | Drosophila Ref1/ALYREF regulates transcription and toxicity associated with ALS/FTD disease etiologies |
| title_short | Drosophila Ref1/ALYREF regulates transcription and toxicity associated with ALS/FTD disease etiologies |
| title_sort | drosophila ref1 alyref regulates transcription and toxicity associated with als ftd disease etiologies |
| topic | ALYREF Ref1 Drosophila Amyotrophic lateral sclerosis (ALS) (Lou Gehrig disease) Ataxin-2 C9orf72 |
| url | http://link.springer.com/article/10.1186/s40478-019-0710-x |
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