Dysferlin and its role in the pathogenesis of muscular dystrophy

Dysferlin and its role in the pathogenesis of muscular dystrophy

Hofhuis, Julia

Dissertation

Angenommen am: 2013-11-19

Erschienen: 2013-11-21

Betreuer: Klinge, Lars PD Dr.

Betreuer: Thoms, Sven PD Dr.

Gutachter: Gärtner, Jutta Prof. Dr.

Gutachter: Schu, Peter Prof. Dr.

Zum Verlinken/Zitieren: http://hdl.handle.net/11858/00-1735-0000-0001-BC76-4

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Name: Dissertation Julia Hofhuis 2013.pdf

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Zusammenfassung

Englisch

Dysferlin is a multi C2 domain protein that belongs to the ferlin family and is localized to the T-tubule system in skeletal muscle fibers. It is involved in skeletal muscle membrane repair, regeneration and T-tubule biogenesis. The precise biochemical function of dysferlin has not been discovered so far, but mutations in the dysferlin gene lead to mucular dystrophy. Preliminary data demonstrated that dysferlin induces tubulated membranes when heterologeously expressed in non-muscle cells. These observations suggested a role of dysferlin in membrane tubulation, and it was the aim of this thesis to further examine the biochemical and cell biological of dysferlin Analysis of dysferlin-induced tubules in non-muscle cells revealed that these structures share biochemical and morphological similarities to T-tubule membranes as they incorporate T-tubule phospholipids and invaginate from the plasma membrane. Full-length dysferlin was required for membrane tubulation, and pathogenic mutations impaired membrane deformation capacity. In vitro, dysferlin induces liposome tubulation which provides direct morphological evidence for a powerful membrane tubulation capacity. In this thesis it was further demonstrated that the alteration in T-tubule morphology of dysferlin-deficient muscle lead to increased Ca2+ release probably through excitation-coupled Ca2+ entry. This effect was not due to a secondary alteration of triad- or T-tubule associated proteins and resulted in increased exercise capacity in juvenile dysferlin-deficient mice similar to the phenotype of presymptomatic patients affected by dysfelin-deficient muscular dystrophy. Also in heart muscle dysferlin was required for a morphologically and functionally intact T-tubule system. Functional alterations in Ca2+ homeostasis were compensated under normal physiological conditions but induced severe arrhythmogenic events in stress situations. Taken together, we provide direct evidence that dysferlin induces membrane tubulation defining a novel function of this protein. The abnormal T-tubule system affects Ca2+ homeostasis in skeletal and heart muscle. These findings may have important clinical implications, and modulation of Ca2+ homesostasis in dysferlin-deficient muscular dystrophy should be investigated as a possible translational therapeutic approach.

Keywords: Dysferlin; Muscular dystrophy