TDP-43 and RNA form amyloid-like myo-granules in regenerating muscle.
Nature
; 563(7732): 508-513, 2018 11.
Article
em En
| MEDLINE
| ID: mdl-30464263
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 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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Regeneração
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RNA Mensageiro
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Músculo Esquelético
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Proteínas de Ligação a DNA
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Proteinopatias TDP-43
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Amiloide
Limite:
Animals
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Female
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Humans
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Male
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article