TDP-43 and RNA form amyloid-like myo-granules in regenerating muscle
| Autor: | Theodore Eugene Ewachiw, Joshua Wheeler, Michael P. Hughes, James Shorter, Edward Gomes, David Eisenberg, Oscar N. Whitney, Kyla A. Britson, Eric D. Nguyen, Thomas E. Lloyd, Aaron M. Johnson, Nicole Dalla Betta, Evan Lester, Bhalchandra S. Rao, Thomas O. Vogler, Bradley B. Olwin, J. Paul Taylor, Roy Parker |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Amyloid RNA-binding protein Protein aggregation TARDBP Sarcomere Article 03 medical and health sciences 0302 clinical medicine mental disorders medicine Regeneration Musculoskeletal System Multidisciplinary Chemistry Regeneration (biology) Skeletal muscle RNA nutritional and metabolic diseases 3. Good health Cell biology nervous system diseases DNA-Binding Proteins 030104 developmental biology medicine.anatomical_structure 030217 neurology & neurosurgery |
| Zdroj: | Nature |
| ISSN: | 1476-4687 0028-0836 |
| Popis: | A dominant histopathological feature in neuromuscular diseases, including amyotrophic lateral sclerosis and inclusion body myopathy, is cytoplasmic aggregation of the RNA-binding protein TDP-43. Although rare mutations in TARDBP-the gene that encodes TDP-43-that lead to protein misfolding often cause protein aggregation, most patients do not have any mutations in TARDBP. Therefore, aggregates of wild-type TDP-43 arise in most patients by an unknown mechanism. Here we show that TDP-43 is an essential protein for normal skeletal muscle formation that unexpectedly forms cytoplasmic, amyloid-like oligomeric assemblies, which we call myo-granules, during regeneration of skeletal muscle in mice and humans. Myo-granules bind to mRNAs that encode sarcomeric proteins and are cleared as myofibres mature. Although myo-granules occur during normal skeletal-muscle regeneration, myo-granules can seed TDP-43 amyloid fibrils in vitro and are increased in a mouse model of inclusion body myopathy. Therefore, increased assembly or decreased clearance of functionally normal myo-granules could be the source of cytoplasmic TDP-43 aggregates that commonly occur in neuromuscular disease. |
| Databáze: | OpenAIRE |
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