The era of cryptic exons: implications for ALS-FTD
Abstract TDP-43 is an RNA-binding protein with a crucial nuclear role in splicing, and mislocalises from the nucleus to the cytoplasm in a range of neurodegenerative disorders. TDP-43 proteinopathy spans a spectrum of incurable, heterogeneous, and increasingly prevalent neurodegenerative diseases, i...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-03-01
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| Series: | Molecular Neurodegeneration |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13024-023-00608-5 |
| _version_ | 1797863563359944704 |
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| author | Puja R. Mehta Anna-Leigh Brown Michael E. Ward Pietro Fratta |
| author_facet | Puja R. Mehta Anna-Leigh Brown Michael E. Ward Pietro Fratta |
| author_sort | Puja R. Mehta |
| collection | DOAJ |
| description | Abstract TDP-43 is an RNA-binding protein with a crucial nuclear role in splicing, and mislocalises from the nucleus to the cytoplasm in a range of neurodegenerative disorders. TDP-43 proteinopathy spans a spectrum of incurable, heterogeneous, and increasingly prevalent neurodegenerative diseases, including the amyotrophic lateral sclerosis and frontotemporal dementia disease spectrum and a significant fraction of Alzheimer’s disease. There are currently no directed disease-modifying therapies for TDP-43 proteinopathies, and no way to distinguish who is affected before death. It is now clear that TDP-43 proteinopathy leads to a number of molecular changes, including the de-repression and inclusion of cryptic exons. Importantly, some of these cryptic exons lead to the loss of crucial neuronal proteins and have been shown to be key pathogenic players in disease pathogenesis (e.g., STMN2), as well as being able to modify disease progression (e.g., UNC13A). Thus, these aberrant splicing events make promising novel therapeutic targets to restore functional gene expression. Moreover, presence of these cryptic exons is highly specific to patients and areas of the brain affected by TDP-43 proteinopathy, offering the potential to develop biomarkers for early detection and stratification of patients. In summary, the discovery of cryptic exons gives hope for novel diagnostics and therapeutics on the horizon for TDP-43 proteinopathies. |
| first_indexed | 2024-04-09T22:38:36Z |
| format | Article |
| id | doaj.art-c2741b5e80194d549e3f338eb6ddeb60 |
| institution | Directory Open Access Journal |
| issn | 1750-1326 |
| language | English |
| last_indexed | 2024-04-09T22:38:36Z |
| publishDate | 2023-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Neurodegeneration |
| spelling | doaj.art-c2741b5e80194d549e3f338eb6ddeb602023-03-22T12:22:24ZengBMCMolecular Neurodegeneration1750-13262023-03-011811910.1186/s13024-023-00608-5The era of cryptic exons: implications for ALS-FTDPuja R. Mehta0Anna-Leigh Brown1Michael E. Ward2Pietro Fratta3Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL Queen Square Motor Neuron Disease CentreDepartment of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL Queen Square Motor Neuron Disease CentreNational Institute of Neurological Disorders and Stroke, NIHDepartment of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL Queen Square Motor Neuron Disease CentreAbstract TDP-43 is an RNA-binding protein with a crucial nuclear role in splicing, and mislocalises from the nucleus to the cytoplasm in a range of neurodegenerative disorders. TDP-43 proteinopathy spans a spectrum of incurable, heterogeneous, and increasingly prevalent neurodegenerative diseases, including the amyotrophic lateral sclerosis and frontotemporal dementia disease spectrum and a significant fraction of Alzheimer’s disease. There are currently no directed disease-modifying therapies for TDP-43 proteinopathies, and no way to distinguish who is affected before death. It is now clear that TDP-43 proteinopathy leads to a number of molecular changes, including the de-repression and inclusion of cryptic exons. Importantly, some of these cryptic exons lead to the loss of crucial neuronal proteins and have been shown to be key pathogenic players in disease pathogenesis (e.g., STMN2), as well as being able to modify disease progression (e.g., UNC13A). Thus, these aberrant splicing events make promising novel therapeutic targets to restore functional gene expression. Moreover, presence of these cryptic exons is highly specific to patients and areas of the brain affected by TDP-43 proteinopathy, offering the potential to develop biomarkers for early detection and stratification of patients. In summary, the discovery of cryptic exons gives hope for novel diagnostics and therapeutics on the horizon for TDP-43 proteinopathies.https://doi.org/10.1186/s13024-023-00608-5Motor neuron diseaseAmyotrophic lateral sclerosisFrontotemporal dementiaTDP-43 proteinopathiesCryptic exonsSplicing |
| spellingShingle | Puja R. Mehta Anna-Leigh Brown Michael E. Ward Pietro Fratta The era of cryptic exons: implications for ALS-FTD Molecular Neurodegeneration Motor neuron disease Amyotrophic lateral sclerosis Frontotemporal dementia TDP-43 proteinopathies Cryptic exons Splicing |
| title | The era of cryptic exons: implications for ALS-FTD |
| title_full | The era of cryptic exons: implications for ALS-FTD |
| title_fullStr | The era of cryptic exons: implications for ALS-FTD |
| title_full_unstemmed | The era of cryptic exons: implications for ALS-FTD |
| title_short | The era of cryptic exons: implications for ALS-FTD |
| title_sort | era of cryptic exons implications for als ftd |
| topic | Motor neuron disease Amyotrophic lateral sclerosis Frontotemporal dementia TDP-43 proteinopathies Cryptic exons Splicing |
| url | https://doi.org/10.1186/s13024-023-00608-5 |
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