TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A
<jats:title>Abstract</jats:title><jats:p>Variants of <jats:italic>UNC13A</jats:italic>, a critical gene for synapse function, increase the risk of amyotrophic lateral sclerosis and frontotemporal dementia<jats:sup>1–3</jats:sup>, two related neurodegenerativ...
| Main Author: | |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | English |
| Published: |
Springer Science and Business Media LLC
2023
|
| Online Access: | https://hdl.handle.net/1721.1/147818 |
| _version_ | 1811085094358614016 |
|---|---|
| author | Fraenkel, Ernest |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Fraenkel, Ernest |
| author_sort | Fraenkel, Ernest |
| collection | MIT |
| description | <jats:title>Abstract</jats:title><jats:p>Variants of <jats:italic>UNC13A</jats:italic>, a critical gene for synapse function, increase the risk of amyotrophic lateral sclerosis and frontotemporal dementia<jats:sup>1–3</jats:sup>, two related neurodegenerative diseases defined by mislocalization of the RNA-binding protein TDP-43<jats:sup>4,5</jats:sup>. Here we show that TDP-43 depletion induces robust inclusion of a cryptic exon in <jats:italic>UNC13A</jats:italic>, resulting in nonsense-mediated decay and loss of UNC13A protein. Two common intronic <jats:italic>UNC13A</jats:italic> polymorphisms strongly associated with amyotrophic lateral sclerosis and frontotemporal dementia risk overlap with TDP-43 binding sites. These polymorphisms potentiate cryptic exon inclusion, both in cultured cells and in brains and spinal cords from patients with these conditions. Our findings, which demonstrate a genetic link between loss of nuclear TDP-43 function and disease, reveal the mechanism by which <jats:italic>UNC13A</jats:italic> variants exacerbate the effects of decreased TDP-43 function. They further provide a promising therapeutic target for TDP-43 proteinopathies.</jats:p> |
| first_indexed | 2024-09-23T13:02:48Z |
| format | Article |
| id | mit-1721.1/147818 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T13:02:48Z |
| publishDate | 2023 |
| publisher | Springer Science and Business Media LLC |
| record_format | dspace |
| spelling | mit-1721.1/1478182023-02-01T03:29:04Z TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A Fraenkel, Ernest Massachusetts Institute of Technology. Department of Biological Engineering <jats:title>Abstract</jats:title><jats:p>Variants of <jats:italic>UNC13A</jats:italic>, a critical gene for synapse function, increase the risk of amyotrophic lateral sclerosis and frontotemporal dementia<jats:sup>1–3</jats:sup>, two related neurodegenerative diseases defined by mislocalization of the RNA-binding protein TDP-43<jats:sup>4,5</jats:sup>. Here we show that TDP-43 depletion induces robust inclusion of a cryptic exon in <jats:italic>UNC13A</jats:italic>, resulting in nonsense-mediated decay and loss of UNC13A protein. Two common intronic <jats:italic>UNC13A</jats:italic> polymorphisms strongly associated with amyotrophic lateral sclerosis and frontotemporal dementia risk overlap with TDP-43 binding sites. These polymorphisms potentiate cryptic exon inclusion, both in cultured cells and in brains and spinal cords from patients with these conditions. Our findings, which demonstrate a genetic link between loss of nuclear TDP-43 function and disease, reveal the mechanism by which <jats:italic>UNC13A</jats:italic> variants exacerbate the effects of decreased TDP-43 function. They further provide a promising therapeutic target for TDP-43 proteinopathies.</jats:p> 2023-01-31T18:58:45Z 2023-01-31T18:58:45Z 2022 2023-01-31T18:55:58Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/147818 Fraenkel, Ernest. 2022. "TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A." Nature, 603 (7899). en 10.1038/S41586-022-04436-3 Nature Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/ application/pdf Springer Science and Business Media LLC Nature |
| spellingShingle | Fraenkel, Ernest TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A |
| title | TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A |
| title_full | TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A |
| title_fullStr | TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A |
| title_full_unstemmed | TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A |
| title_short | TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A |
| title_sort | tdp 43 loss and als risk snps drive mis splicing and depletion of unc13a |
| url | https://hdl.handle.net/1721.1/147818 |
| work_keys_str_mv | AT fraenkelernest tdp43lossandalsrisksnpsdrivemissplicinganddepletionofunc13a |