Widespread FUS mislocalization is a molecular hallmark of amyotrophic lateral sclerosis
| Autor: | Miha Modic, Jamie S. Mitchell, Jacob Neeves, Jernej Ule, Linda Greensmith, Raphaëlle Luisier, Doaa M Taha, Jia Newcombe, Ione Meyer, Giulia E. Tyzack, Rickie Patani, Nicholas M. Luscombe |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male Cytoplasm amyotrophic lateral sclerosis (ALS) Induced Pluripotent Stem Cells Gene Expression RNA-binding protein Context (language use) Mice Transgenic Biology medicine.disease_cause Biochemistry & Proteomics intron retention 03 medical and health sciences Mice 0302 clinical medicine Ecology Evolution & Ethology medicine Animals Humans Amyotrophic lateral sclerosis Nuclear export signal Computational & Systems Biology Cell Nucleus Mutation FOS: Clinical medicine Stem Cells Amyotrophic Lateral Sclerosis Intron Neurosciences Cell Biology Tumour Biology medicine.disease RNA binding protein 3. Good health Cell biology fused in sarcoma FUS Mice Inbred C57BL Cell nucleus 030104 developmental biology medicine.anatomical_structure RNA-Binding Protein FUS Female Neurology (clinical) Genetics & Genomics 030217 neurology & neurosurgery Biomarkers Reports |
| Zdroj: | Brain |
| ISSN: | 0006-8950 |
| Popis: | See Vidal and Atkin (doi:10.1093/brain/awz256) for a scientific commentary on this article. ALS remains incurable due to an incomplete understanding of its molecular pathogenesis. Tyzack, Luisier et al. report that FUS protein, previously thought to mislocalise only in patients with FUS mutations, is also mislocalised in many cases of sporadic ALS. They further propose an underlying molecular mechanism for the mislocalisation. Mutations causing amyotrophic lateral sclerosis (ALS) clearly implicate ubiquitously expressed and predominantly nuclear RNA binding proteins, which form pathological cytoplasmic inclusions in this context. However, the possibility that wild-type RNA binding proteins mislocalize without necessarily becoming constituents of cytoplasmic inclusions themselves remains relatively unexplored. We hypothesized that nuclear-to-cytoplasmic mislocalization of the RNA binding protein fused in sarcoma (FUS), in an unaggregated state, may occur more widely in ALS than previously recognized. To address this hypothesis, we analysed motor neurons from a human ALS induced-pluripotent stem cell model caused by the VCP mutation. Additionally, we examined mouse transgenic models and post-mortem tissue from human sporadic ALS cases. We report nuclear-to-cytoplasmic mislocalization of FUS in both VCP-mutation related ALS and, crucially, in sporadic ALS spinal cord tissue from multiple cases. Furthermore, we provide evidence that FUS protein binds to an aberrantly retained intron within the SFPQ transcript, which is exported from the nucleus into the cytoplasm. Collectively, these data support a model for ALS pathogenesis whereby aberrant intron retention in SFPQ transcripts contributes to FUS mislocalization through their direct interaction and nuclear export. In summary, we report widespread mislocalization of the FUS protein in ALS and propose a putative underlying mechanism for this process. |
| Databáze: | OpenAIRE |
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