Dysferlin in skeletal and heart muscle: from trafficking to therapy
von Kristina Bersch
Datum der mündl. Prüfung:2017-08-24
Betreuer:PD Dr. Sven Thoms
Gutachter:PD Dr. Sven Thoms
Gutachter:Prof. Dr. Wolfgang Brück
EnglischDysferlinopathies are a heterogeneous group of congenital muscle disorders characterized by late-onset muscular dystrophy and increased muscle prowess before onset of symptoms. Mutations in the DYSF gene encoding the protein dysferlin have been identified as the common genetic cause of this rare disease spectrum. However, little is known about the pathomechanism leading to muscle degeneration and therefore, no curative treatment is available. Dysferlin is a tail-anchored multi-C2 domain protein belonging to the ferlin protein family. For a long time, it has mainly been implicated in membrane repair. In recent years, new evidence uncovered an additional and fundamental role for dysferlin: the formation of the T-tubule system in skeletal muscle. The aim of this study was to further elucidate the cellular role in skeletal and heart muscle and the trafficking of dysferlin. This would help to reveal the molecular pathomechanism of dysferlin-deficient muscular dystrophy and give the possibility to identify new targets for the development of therapeutic approaches. The finding of an abnormal T-tubule system in developing dysferlinopathy patient myotubes suggests that dysferlin is essential during a very early stage of T-tubule biogenesis in skeletal muscle. Not only the T-tubule system in skeletal muscle, but also the cardiac tubular system of dysferlin-deficient mice is altered with loss and axialization of membrane tubules. This finding, together with the localization and increased expression of dysferlin at the developing T-tubule system in cardiomyocytes, support the role of dysferlin as a key player of cardiac T-tubule biogenesis. Furthermore, these findings may explain the pathology of dysferlin-deficiency in skeletal and heart muscle. The investigation of the cellular trafficking shows that mutated dysferlin is retained in the endoplasmic reticulum or Golgi network and provides evidence that functional dysferlin follows the secretory pathway to reach the plasma and T-tubule membrane. Treatment with the chemical chaperone 4-phenylbutyrate (PBA) increases the steady-state protein levels and partially rescues functional deficits of dysferlin mutants. Thus, PBA might be a potential therapeutic for the treatment of dysferlinopathy. Another therapeutic approach is the induction of translational readthrough by aminoglycosides in patients harboring nonsense DYSF mutations. The systematic analysis of readthrough induction for all recurrent DYSF nonsense mutations revealed a high variety of readthrough efficiency and might provide a suitable prediction for the treatability of dysferlinopathy patients. This gives the possibility to selectively treat patients with high therapeutic potential as aminoglycosides are associated with severe adverse effects.
Keywords: dysferlin; dysferlinopathy; heart; skeletal muscle; trafficking; readthrough