TDP-43 and RNA form amyloid-like myo-granules in regenerating muscle. (22nd November 2018)

• Record Type: Journal Article
• Authors: Vogler, Thomas; Wheeler, Joshua; Nguyen, Eric; Hughes, Michael; Britson, Kyla; Lester, Evan; Rao, Bhalchandra; Betta, Nicole; Whitney, Oscar; Ewachiw, Theodore; Gomes, Edward; Shorter, James; Lloyd, Thomas; Eisenberg, David; Taylor, J.; Johnson, Aaron; Olwin, Bradley; Parker, Roy
• Is Part Of: Nature. Volume 563:Number 7732(2018)
• Page Start: 508
• Page End: 513
• Publication Date: 2018-11-22
• Subjects: Science -- Periodicals; 505
• DOI: 10.1038/s41586-018-0665-2
• Languages: English
• ISSNs: 0028-0836

Abstract

Abstract 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 inTARDBP —the gene that encodes TDP-43—that lead to protein misfolding often cause protein aggregation, most patients do not have any mutations inTARDBP . 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. Cytoplasmic, amyloid-like oligomeric assemblies that contain TDP-43 are increased in damaged tissues with elevated regeneration, thereby enhancing the possibility of amyloid fibre formation and/or aggregation of TDP-43 in disease.