Suppression of C9orf72 RNA repeat-induced neurotoxicity by the ALS-associated RNA-binding protein Zfp106
Expanded GGGGCC repeats in the first intron of the C9orf72 gene represent the most common cause of familial amyotrophic lateral sclerosis (ALS), but the mechanisms underlying repeat-induced disease remain incompletely resolved. One proposed gain-of-function mechanism is that repeat-containing RNA fo...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2017-01-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/19032 |
| _version_ | 1811227636074020864 |
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| author | Barbara Celona John von Dollen Sarat C Vatsavayai Risa Kashima Jeffrey R Johnson Amy A Tang Akiko Hata Bruce L Miller Eric J Huang Nevan J Krogan William W Seeley Brian L Black |
| author_facet | Barbara Celona John von Dollen Sarat C Vatsavayai Risa Kashima Jeffrey R Johnson Amy A Tang Akiko Hata Bruce L Miller Eric J Huang Nevan J Krogan William W Seeley Brian L Black |
| author_sort | Barbara Celona |
| collection | DOAJ |
| description | Expanded GGGGCC repeats in the first intron of the C9orf72 gene represent the most common cause of familial amyotrophic lateral sclerosis (ALS), but the mechanisms underlying repeat-induced disease remain incompletely resolved. One proposed gain-of-function mechanism is that repeat-containing RNA forms aggregates that sequester RNA binding proteins, leading to altered RNA metabolism in motor neurons. Here, we identify the zinc finger protein Zfp106 as a specific GGGGCC RNA repeat-binding protein, and using affinity purification-mass spectrometry, we show that Zfp106 interacts with multiple other RNA binding proteins, including the ALS-associated factors TDP-43 and FUS. We also show that Zfp106 knockout mice develop severe motor neuron degeneration, which can be suppressed by transgenic restoration of Zfp106 specifically in motor neurons. Finally, we show that Zfp106 potently suppresses neurotoxicity in a Drosophila model of C9orf72 ALS. Thus, these studies identify Zfp106 as an RNA binding protein with important implications for ALS. |
| first_indexed | 2024-04-12T09:45:31Z |
| format | Article |
| id | doaj.art-7f808a4696024cde9c96b1dbd8a38c0c |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T09:45:31Z |
| publishDate | 2017-01-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-7f808a4696024cde9c96b1dbd8a38c0c2022-12-22T03:37:57ZengeLife Sciences Publications LtdeLife2050-084X2017-01-01610.7554/eLife.19032Suppression of C9orf72 RNA repeat-induced neurotoxicity by the ALS-associated RNA-binding protein Zfp106Barbara Celona0John von Dollen1Sarat C Vatsavayai2Risa Kashima3Jeffrey R Johnson4Amy A Tang5Akiko Hata6Bruce L Miller7Eric J Huang8Nevan J Krogan9William W Seeley10Brian L Black11https://orcid.org/0000-0002-6664-8913Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United StatesDepartment of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United StatesDepartment of Neurology, University of California, San Francisco, San Francisco, United StatesCardiovascular Research Institute, University of California, San Francisco, San Francisco, United StatesDepartment of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United StatesDepartment of Pathology, University of California, San Francisco, San Francisco, United StatesCardiovascular Research Institute, University of California, San Francisco, San Francisco, United StatesDepartment of Neurology, University of California, San Francisco, San Francisco, United StatesDepartment of Pathology, University of California, San Francisco, San Francisco, United StatesDepartment of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United StatesDepartment of Neurology, University of California, San Francisco, San Francisco, United States; Department of Pathology, University of California, San Francisco, San Francisco, United StatesCardiovascular Research Institute, University of California, San Francisco, San Francisco, United States; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United StatesExpanded GGGGCC repeats in the first intron of the C9orf72 gene represent the most common cause of familial amyotrophic lateral sclerosis (ALS), but the mechanisms underlying repeat-induced disease remain incompletely resolved. One proposed gain-of-function mechanism is that repeat-containing RNA forms aggregates that sequester RNA binding proteins, leading to altered RNA metabolism in motor neurons. Here, we identify the zinc finger protein Zfp106 as a specific GGGGCC RNA repeat-binding protein, and using affinity purification-mass spectrometry, we show that Zfp106 interacts with multiple other RNA binding proteins, including the ALS-associated factors TDP-43 and FUS. We also show that Zfp106 knockout mice develop severe motor neuron degeneration, which can be suppressed by transgenic restoration of Zfp106 specifically in motor neurons. Finally, we show that Zfp106 potently suppresses neurotoxicity in a Drosophila model of C9orf72 ALS. Thus, these studies identify Zfp106 as an RNA binding protein with important implications for ALS.https://elifesciences.org/articles/19032zinc finger proteinRNA binding proteinknockout animalstransgenic animalsneurodegeneration |
| spellingShingle | Barbara Celona John von Dollen Sarat C Vatsavayai Risa Kashima Jeffrey R Johnson Amy A Tang Akiko Hata Bruce L Miller Eric J Huang Nevan J Krogan William W Seeley Brian L Black Suppression of C9orf72 RNA repeat-induced neurotoxicity by the ALS-associated RNA-binding protein Zfp106 eLife zinc finger protein RNA binding protein knockout animals transgenic animals neurodegeneration |
| title | Suppression of C9orf72 RNA repeat-induced neurotoxicity by the ALS-associated RNA-binding protein Zfp106 |
| title_full | Suppression of C9orf72 RNA repeat-induced neurotoxicity by the ALS-associated RNA-binding protein Zfp106 |
| title_fullStr | Suppression of C9orf72 RNA repeat-induced neurotoxicity by the ALS-associated RNA-binding protein Zfp106 |
| title_full_unstemmed | Suppression of C9orf72 RNA repeat-induced neurotoxicity by the ALS-associated RNA-binding protein Zfp106 |
| title_short | Suppression of C9orf72 RNA repeat-induced neurotoxicity by the ALS-associated RNA-binding protein Zfp106 |
| title_sort | suppression of c9orf72 rna repeat induced neurotoxicity by the als associated rna binding protein zfp106 |
| topic | zinc finger protein RNA binding protein knockout animals transgenic animals neurodegeneration |
| url | https://elifesciences.org/articles/19032 |
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