The C9ORF72 GGGGCC expansion forms RNA G-quadruplex inclusions and sequesters hnRNP H to disrupt splicing in ALS brains
An expanded GGGGCC hexanucleotide in C9ORF72 (C9) is the most frequent known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). It has been proposed that expanded transcripts adopt G-quadruplex (G-Q) structures and associate with proteins, but whether this occurs and con...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2016-09-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/17820 |
| _version_ | 1811200131025862656 |
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| author | Erin G Conlon Lei Lu Aarti Sharma Takashi Yamazaki Timothy Tang Neil A Shneider James L Manley |
| author_facet | Erin G Conlon Lei Lu Aarti Sharma Takashi Yamazaki Timothy Tang Neil A Shneider James L Manley |
| author_sort | Erin G Conlon |
| collection | DOAJ |
| description | An expanded GGGGCC hexanucleotide in C9ORF72 (C9) is the most frequent known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). It has been proposed that expanded transcripts adopt G-quadruplex (G-Q) structures and associate with proteins, but whether this occurs and contributes to disease is unknown. Here we show first that the protein that predominantly associates with GGGGCC repeat RNA in vitro is the splicing factor hnRNP H, and that this interaction is linked to G-Q formation. We then show that G-Q RNA foci are more abundant in C9 ALS patient fibroblasts and astrocytes compared to those without the expansion, and more frequently colocalize with hnRNP H. Importantly, we demonstrate dysregulated splicing of multiple known hnRNP H-target transcripts in C9 patient brains, which correlates with elevated insoluble hnRNP H/G-Q aggregates. Together, our data implicate C9 expansion-mediated sequestration of hnRNP H as a significant contributor to neurodegeneration in C9 ALS/FTD. |
| first_indexed | 2024-04-12T01:59:41Z |
| format | Article |
| id | doaj.art-d8128c60d131440f9b78ad600e2de93a |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T01:59:41Z |
| publishDate | 2016-09-01 |
| publisher | eLife Sciences Publications Ltd |
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| series | eLife |
| spelling | doaj.art-d8128c60d131440f9b78ad600e2de93a2022-12-22T03:52:43ZengeLife Sciences Publications LtdeLife2050-084X2016-09-01510.7554/eLife.17820The C9ORF72 GGGGCC expansion forms RNA G-quadruplex inclusions and sequesters hnRNP H to disrupt splicing in ALS brainsErin G Conlon0Lei Lu1Aarti Sharma2https://orcid.org/0000-0002-4907-2174Takashi Yamazaki3Timothy Tang4Neil A Shneider5James L Manley6https://orcid.org/0000-0002-8341-1459Department of Biological Sciences, Columbia University, New York, United StatesDepartment of Neurology, Columbia University Medical Center, New York, United StatesDepartment of Neurology, Columbia University Medical Center, New York, United StatesDepartment of Biological Sciences, Columbia University, New York, United StatesDepartment of Biological Sciences, Columbia University, New York, United StatesDepartment of Neurology, Columbia University Medical Center, New York, United StatesDepartment of Biological Sciences, Columbia University, New York, United StatesAn expanded GGGGCC hexanucleotide in C9ORF72 (C9) is the most frequent known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). It has been proposed that expanded transcripts adopt G-quadruplex (G-Q) structures and associate with proteins, but whether this occurs and contributes to disease is unknown. Here we show first that the protein that predominantly associates with GGGGCC repeat RNA in vitro is the splicing factor hnRNP H, and that this interaction is linked to G-Q formation. We then show that G-Q RNA foci are more abundant in C9 ALS patient fibroblasts and astrocytes compared to those without the expansion, and more frequently colocalize with hnRNP H. Importantly, we demonstrate dysregulated splicing of multiple known hnRNP H-target transcripts in C9 patient brains, which correlates with elevated insoluble hnRNP H/G-Q aggregates. Together, our data implicate C9 expansion-mediated sequestration of hnRNP H as a significant contributor to neurodegeneration in C9 ALS/FTD.https://elifesciences.org/articles/17820amyotrophic lateral sclerosisRNA structuredisease mechanism |
| spellingShingle | Erin G Conlon Lei Lu Aarti Sharma Takashi Yamazaki Timothy Tang Neil A Shneider James L Manley The C9ORF72 GGGGCC expansion forms RNA G-quadruplex inclusions and sequesters hnRNP H to disrupt splicing in ALS brains eLife amyotrophic lateral sclerosis RNA structure disease mechanism |
| title | The C9ORF72 GGGGCC expansion forms RNA G-quadruplex inclusions and sequesters hnRNP H to disrupt splicing in ALS brains |
| title_full | The C9ORF72 GGGGCC expansion forms RNA G-quadruplex inclusions and sequesters hnRNP H to disrupt splicing in ALS brains |
| title_fullStr | The C9ORF72 GGGGCC expansion forms RNA G-quadruplex inclusions and sequesters hnRNP H to disrupt splicing in ALS brains |
| title_full_unstemmed | The C9ORF72 GGGGCC expansion forms RNA G-quadruplex inclusions and sequesters hnRNP H to disrupt splicing in ALS brains |
| title_short | The C9ORF72 GGGGCC expansion forms RNA G-quadruplex inclusions and sequesters hnRNP H to disrupt splicing in ALS brains |
| title_sort | c9orf72 ggggcc expansion forms rna g quadruplex inclusions and sequesters hnrnp h to disrupt splicing in als brains |
| topic | amyotrophic lateral sclerosis RNA structure disease mechanism |
| url | https://elifesciences.org/articles/17820 |
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