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

The term "desminopathies" stands for a group of familial and sporadic myopathies and cardiomyopathies, which are caused by mutations in the human desmin gene. Desminopathies belong to the group of rare human diseases with less than 5 affected individuals in 10,000. The majority of desminopathies follow an autosomal dominant trait of inheritance. In addition, rare autosomal recessive cases as well as an increasing number of sporadic desminopathies have been described. The autosomal recessive cases may further be subdivided into those with maintained expression of mutant desmin and others with a complete lack of desmin. We previously generated data from man and mouse demonstrating that the complete lack as well as the sole expression of mutant R349P desmin impair the structural and functional integrity of neuromuscular endplates thus contributing to the clinical sign of muscle weakness in desminopathies.In the present project we aim to clarify the relationship between wildtype and mutant desmin as well as the lack of desmin, and NMJ morphology and function in more detail. Since comprehensive studies on human skeletal muscle tissue are strongly hampered by the availability of appropriate biopsy specimens, we will exploit our patient-mimicking desminopathy mouse models (desmin-null, hetero- and homozygous R349P desmin knock-in) as well as the corresponding immortalized desminopathy myoblast cultures by a comprehensive, multi-level analysis.Our project will address the following major research questions: 1) What are the effects of (a) the lack of desmin, (b) the sole expression of mutant desmin R349P, (c) the mixed expression of mutant and wildtype desmin, on the structure and integrity of NMJs?2) How does (a) the lack of desmin, (b) the sole expression of mutant desmin R349P, (c) the mixed expression of mutant and wildtype desmin, affect neuromuscular transmission?3) Are immortalized wildtype and desminopathy myoblast cultures different regarding the agrin-dependent aggregation of nicotinic acetylcholine receptors (AChRs), in comparison with non-immortalized wildtype and desmin-null cells?4) In which way is desmin involved in the aggregation of AChRs at the neuromuscular junction? Does it influence prepattering, formation and maintenance of AChR aggregation?5) Does desmin directly interact with postsynaptic proteins? Are any of these interactions compromised in the presence of mutant R349P desmin? Does the lack of desmin or the presence of mutant R349P desmin interfere with phosphorylation patterns of postsynaptic proteins?6) How is desmin involved in signaling pathways related to NMJs? How are these pathways affected in the absence of desmin or in the presence of mutant R349P?7) What is the molecular mechanism of salbutamol-mediated rescue of the NMJ morphology?

• DFG Programme: Research Grants