Neuromuscular endplate pathology in autosomal dominant and recessive desminopathies

• Applicants: Professor Dr. Said Hashemolhosseini; Professor Dr. Rolf Schröder
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Pathology
• Term: from 2018 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 413238049

• Final Report Year: 2024

Final Report Abstract

Mutations in the human desmin gene cause a clinically broad spectrum of rare skeletal and cardiac muscle diseases. The vast majority of desminopathies follows an autosomal dominant pattern of inheritance. The very rare autosomal recessive cases can be further subdivided into a group with preserved desmin and a group with abolished desmin expression. There are currently no treatment options available for this clinically progressive and often fatal disease entity. Previous studies have shown that desmin is enriched in the area of the neuromuscular endplates and that patients with a lack of desmin can develop a myasthenic syndrome in addition to myopathy and cardiomyopathy. The aim of the funded project was to study neuromuscular endplate pathology in desminopathies in more detail. Since human tissue was not available due to the rarity of the disease, we analysed skeletal muscle tissue from desmin knock-out and hetero- and homozygous R349P desmin knock-in mice. Our morphological studies showed that the neuromuscular endplates in the soleus muscle of desmin knock-out mice were enlarged and fragmented and that these changes were associated with increased transcript levels of the acetylcholine receptor genes, especially the gamma-subunit. These results are very similar to previously published data in homozygous R349P desmin knock-in mice. Electrophysiological studies in desmin knock-out mice further showed a pathological reduction of nerve-dependent endplate potentials and an increased rise time of nerveindependent miniature endplate potentials. Together with the published cases of patients with recessive desminopathies and myasthenic syndromes, our work in desmin knock-out and homozygous R349P desmin knock-in mice demonstrates that both the absence and the isolated expression of mutant desmin leads to pathological alterations of the structural and functional integrity of neuromuscular endplates. As a clinical consequence, all patients with recessive desminopathies should specifically be examined for the presence of a myasthenic syndrome. Since salbutamol and physiostigmine treatment resulted in a significant improvement of myasthenic symptoms in some of the published patients with recessive desminopathies, this targeted screening is of great therapeutic relevance.

Publications

• Lack of Desmin in Mice Causes Structural and Functional Disorders of Neuromuscular Junctions. Frontiers in Molecular Neuroscience, 13.
  Eiber, Nane; Fröb, Franziska; Schowalter, Mirjam; Thiel, Christian; Clemen, Christoph S.; Schröder, Rolf & Hashemolhosseini, Said
  
• The desmin mutation R349P increases contractility and fragility of stem cell‐generated muscle micro‐tissues. Neuropathology and Applied Neurobiology, 48(3).
  Spörrer, Marina; Kah, Delf; Gerum, Richard C.; Reischl, Barbara; Huraskin, Danyil; Dessalles, Claire A.; Schneider, Werner; Goldmann, Wolfgang H.; Herrmann, Harald; Thievessen, Ingo; Clemen, Christoph S.; Friedrich, Oliver; Hashemolhosseini, Said; Schröder, Rolf & Fabry, Ben
  
• In Adult Skeletal Muscles, the Co-Receptors of Canonical Wnt Signaling, Lrp5 and Lrp6, Determine the Distribution and Size of Fiber Types, and Structure and Function of Neuromuscular Junctions. Cells, 11(24), 3968.
  Gessler, Lea; Kurtek, Christopher; Merholz, Mira; Jian, Yongzhi & Hashemolhosseini, Said
  
• The YAP1/TAZ-TEAD transcriptional network regulates gene expression at neuromuscular junctions in skeletal muscle fibers. Nucleic Acids Research, 52(2), 600-624.
  Gessler, Lea; Huraskin, Danyil; Jian, Yongzhi; Eiber, Nane; Hu, Zhaoyong; Prószyński, Tomasz J. & Hashemolhosseini, Said
  
• Crosstalk among canonical Wnt and Hippo pathway members in skeletal muscle and at the neuromuscular junction. Neural Regeneration Research, 20(9), 2464-2479.
  Hashemolhosseini, Said & Gessler, Lea
  
• Deciphering the regulatory pathways in skeletal muscle lineage organized by the YAP1/TAZ-TEAD transcriptional network. openRxiv.
  Gessler, Lea; Siudzińska, Anna; Prószyński, Tomasz J.; Sandri, Marco; von Eyss, Björn & Hashemolhosseini, Said
  
• Integrated data from R405W desmin knock-in mice highlight alterations of mitochondrial function, protein quality control, and myofibrillar structure in the initial stages of myofibrillar myopathy. openRxiv.
  Batonnet-Pichon, Sabrina; Delort, Florence; Lilienbaum, Alain; Berwanger, Carolin; Schultheis, Dorothea; Schlötzer-Schrehardt, Ursula; Schmidt, Andreas; Uebe, Steffen; Baiche, Yosra; Eisenack, Tom J.; Trentini, Débora Broch; Mallek, Markus; Mill, Leonid; Ferreiro, Ana; Eberhard, Bettina; Lücke, Thomas; Krüger, Markus; Thiel, Christian; Schröder, Rolf & Clemen, Christoph S.
  
• The impact of canonical Wnt transcriptional repressors TLE3 and TLE4 on postsynaptic transcription at the neuromuscular junction. Frontiers in Molecular Neuroscience, 17.
  Gessler, Lea; Huraskin, Danyil; Eiber, Nane & Hashemolhosseini, Said