Knockout mice and myocyte cell models to study the pathogenesesis and phenotype rescue of muscular plectinopathies

• Applicant: Professor Dr. Gerhard Wiche
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: from 2009 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 101925924

The most common disease caused by plectin deficiency, epidermolysis bullosa (EB)-MD, is characterized by muscular dystrophy and severe skin blistering. EB-MD patients and plectindeficient mice display massive desmin aggregation, the hallmark of MFM. Our previous studies have shown that the 4 major plectin isoforms expressed in muscle are crucial for the integrity of myofibers by specifically targeting and anchoring desmin IF networks to Z-disks, costameres, mitochondria, and the nuclear/SR membrane system. One of the major achievements of our ongoing project was the establishment of immortalized plectin-deficient myocyte cell lines that spontaneously develop desmin aggregates when differentiated into contractile myotubes. We will take advantage of these systems and of an ample collection of conditional (MCK-Cre/Pax7-Cre) and muscle isoform-specific plectin knockout mouse lines to address the following new objectives: i) analysis of the molecular pathogenesis of plectinrelated MFMs with focus on mechanisms involved in desmin network collapse, isoformspecific interaction partners, and neuromuscular end plate dysfunction; ii) assessment of novel treatment concepts through phenotype rescue (removal of protein aggregates and gene transfer); and iii) analysis of biomechanical properties of plectin-deficient myocytes and muscle fibers.

• DFG Programme: Research Units
• Subproject of: FOR 1228: Molecular Pathogenesis of Myofibrillar Myopathies
• International Connection: Austria