TDP-43-regulated cryptic RNAs accumulate in Alzheimer’s disease brains
Abstract Background Inclusions of TAR DNA-binding protein 43 kDa (TDP-43) has been designated limbic-predominant, age-related TDP-43 encephalopathy (LATE), with or without co-occurrence of Alzheimer’s disease (AD). Approximately, 30–70% AD cases present TDP-43 proteinopathy (AD-TDP), and a greater d...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2023-08-01
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| Series: | Molecular Neurodegeneration |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13024-023-00646-z |
| _version_ | 1797556440996511744 |
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| author | Virginia Estades Ayuso Sarah Pickles Tiffany Todd Mei Yue Karen Jansen-West Yuping Song Jesús González Bejarano Bailey Rawlinson Michael DeTure Neill R. Graff-Radford Bradley F. Boeve David S. Knopman Ronald C. Petersen Dennis W. Dickson Keith A. Josephs Leonard Petrucelli Mercedes Prudencio |
| author_facet | Virginia Estades Ayuso Sarah Pickles Tiffany Todd Mei Yue Karen Jansen-West Yuping Song Jesús González Bejarano Bailey Rawlinson Michael DeTure Neill R. Graff-Radford Bradley F. Boeve David S. Knopman Ronald C. Petersen Dennis W. Dickson Keith A. Josephs Leonard Petrucelli Mercedes Prudencio |
| author_sort | Virginia Estades Ayuso |
| collection | DOAJ |
| description | Abstract Background Inclusions of TAR DNA-binding protein 43 kDa (TDP-43) has been designated limbic-predominant, age-related TDP-43 encephalopathy (LATE), with or without co-occurrence of Alzheimer’s disease (AD). Approximately, 30–70% AD cases present TDP-43 proteinopathy (AD-TDP), and a greater disease severity compared to AD patients without TDP-43 pathology. However, it remains unclear to what extent TDP-43 dysfunction is involved in AD pathogenesis. Methods To investigate whether TDP-43 dysfunction is a prominent feature in AD-TDP cases, we evaluated whether non-conserved cryptic exons, which serve as a marker of TDP-43 dysfunction in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP), accumulate in AD-TDP brains. We assessed a cohort of 192 post-mortem brains from three different brain regions: amygdala, hippocampus, and frontal cortex. Following RNA and protein extraction, qRT-PCR and immunoassays were performed to quantify the accumulation of cryptic RNA targets and phosphorylated TDP-43 pathology, respectively. Results We detected the accumulation of misspliced cryptic or skiptic RNAs of STMN2, KCNQ2, UNC13A, CAMK2B, and SYT7 in the amygdala and hippocampus of AD-TDP cases. The topographic distribution of cryptic RNA accumulation mimicked that of phosphorylated TDP-43, regardless of TDP-43 subtype classification. Further, cryptic RNAs efficiently discriminated AD-TDP cases from controls. Conclusions Overall, our results indicate that cryptic RNAs may represent an intriguing new therapeutic and diagnostic target in AD, and that methods aimed at detecting and measuring these species in patient biofluids could be used as a reliable tool to assess TDP-43 pathology in AD. Our work also raises the possibility that TDP-43 dysfunction and related changes in cryptic splicing could represent a common molecular mechanism shared between AD-TDP and FTLD-TDP. |
| first_indexed | 2024-03-10T17:02:52Z |
| format | Article |
| id | doaj.art-765c9c065e074bc09fdeae894bd6d350 |
| institution | Directory Open Access Journal |
| issn | 1750-1326 |
| language | English |
| last_indexed | 2024-03-10T17:02:52Z |
| publishDate | 2023-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Neurodegeneration |
| spelling | doaj.art-765c9c065e074bc09fdeae894bd6d3502023-11-20T10:54:51ZengBMCMolecular Neurodegeneration1750-13262023-08-0118111310.1186/s13024-023-00646-zTDP-43-regulated cryptic RNAs accumulate in Alzheimer’s disease brainsVirginia Estades Ayuso0Sarah Pickles1Tiffany Todd2Mei Yue3Karen Jansen-West4Yuping Song5Jesús González Bejarano6Bailey Rawlinson7Michael DeTure8Neill R. Graff-Radford9Bradley F. Boeve10David S. Knopman11Ronald C. Petersen12Dennis W. Dickson13Keith A. Josephs14Leonard Petrucelli15Mercedes Prudencio16Department of Neuroscience, Mayo ClinicDepartment of Neuroscience, Mayo ClinicDepartment of Neuroscience, Mayo ClinicDepartment of Neuroscience, Mayo ClinicDepartment of Neuroscience, Mayo ClinicDepartment of Neuroscience, Mayo ClinicDepartment of Neuroscience, Mayo ClinicDepartment of Neuroscience, Mayo ClinicDepartment of Neuroscience, Mayo ClinicDepartment of Neurology, Mayo ClinicDepartment of Neurology, Mayo ClinicDepartment of Neurology, Mayo ClinicDepartment of Neurology, Mayo ClinicDepartment of Neuroscience, Mayo ClinicDepartment of Neurology, Mayo ClinicDepartment of Neuroscience, Mayo ClinicDepartment of Neuroscience, Mayo ClinicAbstract Background Inclusions of TAR DNA-binding protein 43 kDa (TDP-43) has been designated limbic-predominant, age-related TDP-43 encephalopathy (LATE), with or without co-occurrence of Alzheimer’s disease (AD). Approximately, 30–70% AD cases present TDP-43 proteinopathy (AD-TDP), and a greater disease severity compared to AD patients without TDP-43 pathology. However, it remains unclear to what extent TDP-43 dysfunction is involved in AD pathogenesis. Methods To investigate whether TDP-43 dysfunction is a prominent feature in AD-TDP cases, we evaluated whether non-conserved cryptic exons, which serve as a marker of TDP-43 dysfunction in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP), accumulate in AD-TDP brains. We assessed a cohort of 192 post-mortem brains from three different brain regions: amygdala, hippocampus, and frontal cortex. Following RNA and protein extraction, qRT-PCR and immunoassays were performed to quantify the accumulation of cryptic RNA targets and phosphorylated TDP-43 pathology, respectively. Results We detected the accumulation of misspliced cryptic or skiptic RNAs of STMN2, KCNQ2, UNC13A, CAMK2B, and SYT7 in the amygdala and hippocampus of AD-TDP cases. The topographic distribution of cryptic RNA accumulation mimicked that of phosphorylated TDP-43, regardless of TDP-43 subtype classification. Further, cryptic RNAs efficiently discriminated AD-TDP cases from controls. Conclusions Overall, our results indicate that cryptic RNAs may represent an intriguing new therapeutic and diagnostic target in AD, and that methods aimed at detecting and measuring these species in patient biofluids could be used as a reliable tool to assess TDP-43 pathology in AD. Our work also raises the possibility that TDP-43 dysfunction and related changes in cryptic splicing could represent a common molecular mechanism shared between AD-TDP and FTLD-TDP.https://doi.org/10.1186/s13024-023-00646-zTDP-43Alzheimer’s diseaseCryptic RNALATESTMN2 |
| spellingShingle | Virginia Estades Ayuso Sarah Pickles Tiffany Todd Mei Yue Karen Jansen-West Yuping Song Jesús González Bejarano Bailey Rawlinson Michael DeTure Neill R. Graff-Radford Bradley F. Boeve David S. Knopman Ronald C. Petersen Dennis W. Dickson Keith A. Josephs Leonard Petrucelli Mercedes Prudencio TDP-43-regulated cryptic RNAs accumulate in Alzheimer’s disease brains Molecular Neurodegeneration TDP-43 Alzheimer’s disease Cryptic RNA LATE STMN2 |
| title | TDP-43-regulated cryptic RNAs accumulate in Alzheimer’s disease brains |
| title_full | TDP-43-regulated cryptic RNAs accumulate in Alzheimer’s disease brains |
| title_fullStr | TDP-43-regulated cryptic RNAs accumulate in Alzheimer’s disease brains |
| title_full_unstemmed | TDP-43-regulated cryptic RNAs accumulate in Alzheimer’s disease brains |
| title_short | TDP-43-regulated cryptic RNAs accumulate in Alzheimer’s disease brains |
| title_sort | tdp 43 regulated cryptic rnas accumulate in alzheimer s disease brains |
| topic | TDP-43 Alzheimer’s disease Cryptic RNA LATE STMN2 |
| url | https://doi.org/10.1186/s13024-023-00646-z |
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