Article ; Online: Aberrant NOVA1 function disrupts alternative splicing in early stages of amyotrophic lateral sclerosis.
2022 Volume 144, Issue 3, Page(s) 413–435
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by aberrant alternative splicing (AS). Nuclear loss and cytoplasmic accumulation of the splicing factor TDP-43 in motor neurons (MN) are hallmarks of ALS at late stages of the disease. ... ...
| Abstract | Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by aberrant alternative splicing (AS). Nuclear loss and cytoplasmic accumulation of the splicing factor TDP-43 in motor neurons (MN) are hallmarks of ALS at late stages of the disease. However, it is unknown if altered AS is present before TDP-43 pathology occurs. Here, we investigate altered AS and its origins in early stages of ALS using human induced pluripotent stem cell-derived motor neurons (MNs) from sporadic and familial ALS patients. We find high levels of the RNA-binding proteins NOVA1, NOVA2, and RBFOX2 in the insoluble protein fractions and observe that AS events in ALS-associated MNs are enriched for binding sites of these proteins. Our study points to an early disrupted function of NOVA1 that drives AS changes in a complex fashion, including events caused by a consistent loss of NOVA1 function. NOVA1 exhibits increased cytoplasmic protein levels in early stage MNs without TDP-43 pathology in ALS postmortem tissue. As nuclear TDP-43 protein level depletes, NOVA1 is reduced. Potential indications for a reduction of NOVA1 also came from mice over-expressing TDP-43 lacking its nuclear localization signal and iPSC-MN stressed with puromycin. This study highlights that additional RBP-RNA perturbations in ALS occur in parallel to TDP-43. |
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| MeSH term(s) | Alternative Splicing/genetics ; Amyotrophic Lateral Sclerosis/genetics ; Amyotrophic Lateral Sclerosis/metabolism ; Amyotrophic Lateral Sclerosis/pathology ; Animals ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Humans ; Induced Pluripotent Stem Cells/metabolism ; Mice ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; Neuro-Oncological Ventral Antigen/genetics ; Neuro-Oncological Ventral Antigen/metabolism ; Nuclear Proteins/genetics ; RNA Splicing Factors/genetics ; RNA Splicing Factors/metabolism ; RNA-Binding Proteins/genetics ; RNA-Binding Proteins/metabolism ; Repressor Proteins/genetics |
| Chemical Substances | DNA-Binding Proteins ; NOVA1 protein, human ; NOVA2 protein, human ; Nerve Tissue Proteins ; Neuro-Oncological Ventral Antigen ; Nova1 protein, mouse ; Nuclear Proteins ; RBFOX2 protein, human ; RNA Splicing Factors ; RNA-Binding Proteins ; Rbfox2 protein, mouse ; Repressor Proteins ; TARDBP protein, human ; TDP-43 protein, mouse |
| Language | English |
| Publishing date | 2022-07-01 |
| Publishing country | Germany |
| Document type | Journal Article |
| ZDB-ID | 1079-0 |
| ISSN | 1432-0533 ; 0001-6322 |
| ISSN (online) | 1432-0533 |
| ISSN | 0001-6322 |
| DOI | 10.1007/s00401-022-02450-3 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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