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Abnormal TDP-43 and FUS proteins in muscles of sporadic IBM: similarities in a TARDBP-linked ALS patient
  1. Aurelio Hernandez Lain1,
  2. Stéphanie Millecamps2,
  3. Odile Dubourg3,4,
  4. François Salachas5,
  5. Gaëlle Bruneteau5,
  6. Lucette Lacomblez4,5,
  7. Eric LeGuern2,6,
  8. Danielle Seilhean2,3,
  9. Charles Duyckaerts2,3,
  10. Vincent Meininger4,5,
  11. Jacques Mallet2,
  12. Pierre-François Pradat5
  1. 1Servicio Anatomia Patológica, Neuropatologia, Madrid, Spain
  2. 2Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière, INSERM UMRS975, CNRS UMR7225, Université Pierre et Marie Curie-Paris 6, Hôpital Pitié-Salpêtrière, Paris, France
  3. 3Laboratoire de Neuropathologie, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France
  4. 4Université Pierre et Marie Curie-Paris 06, Paris, France
  5. 5Assistance Publique Hôpitaux de Paris (AP-HP), Fédération des Maladies du Système Nerveux, Centre de référence maladies rares SLA, Hôpital Pitié-Salpêtrière, Paris, France
  6. 6AP-HP, Département de Génétique et Cytogénétique, Unité Fonctionnelle de neurogénétique moléculaire et cellulaire, Hôpital Pitié-Salpêtrière, Paris, France
  1. Correspondence toDr Pierre-François Pradat, Fédération des Maladies du Système Nerveux, Bât Paul Castaigne, Hôpital Pitié-Salpêtrière, 83 bd de l'Hôpital, 75013 Paris, France; pierre-francois.pradat{at}psl.aphp.fr

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Introduction

Abnormal protein deposits are observed in the cytoplasm of sporadic inclusion body myositis (s-IBM) muscle. A number of proteins known to be included in s-IBM aggregates have also been described in various neurodegenerative diseases, including ubiquitin, β amyloid peptide, α-synuclein, phosphorylated τ and TAR DNA-binding protein (TDP-43).

In the central nervous system (CNS), TDP-43 aggregates are characteristic of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive neuronal inclusions. Numerous dominant mutations in the TARDBP gene encoding TDP-43 protein have been reported in ALS cases, demonstrating that TDP-43 abnormalities could directly trigger neurodegeneration. The recent discovery of mutations in the gene encoding Fused in Sarcoma (FUS) protein, which shares functional and structural homology with TDP-43, has strengthened the prominence of gene expression-mediating proteins in ALS pathogenesis. Whether muscle TDP-43 aggregates observed in s-IBM are just trashed protein, or whether they are pathogenic, particularly trough RNA metabolism disturbances, remains unknown.

We hypothesised that FUS protein could be altered in TDP-43 positive muscles of s-IBM. For this purpose, we investigated the protein muscle expression of TDP-43 and FUS in s-IBM compared to sporadic amyotrophic lateral sclerosis (SALS) patients (including one patient with TARDBP gene mutation) and controls. We report abnormal FUS and TDP-43 fragments in s-IBM and TARDBP-linked disease.

Methods

Five patients with s-IBM, five patients with …

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