Lilli Winter is a senior researcher at the Neuromuscular Research Department, where she is leading her own project funded by the FWF. She is investigating molecular mechanisms of muscular dystrophies (MDs), a heterogeneous group of disorders characterized by progressive degeneration of skeletal muscle. She is focusing on muscle diseases (myofibrillar myopathies, MFM) related to dysfunctional expression or loss of plectin and desmin. All MFM show a progressive clinical course, lead to severe physical disability and premature death. The knowledge of the precise molecular mechanisms that translate MFM-causing gene mutations into the myopathic phenotype is still limited, but critical for the understanding of patients’ needs and the development of treatments.
Plectin, a cytoskeletal linker protein with a multitude of functions affecting various cellular processes, interlinks intermediate filaments (IFs) with each other and anchors them to sites of strategic importance for the organization and performance of cells. Mutations in the human plectin gene (PLEC) cause epidermolysis bullosa simplex with muscular dystrophy (EBS-MD), an autosomal recessive skin blistering disorder associated with progressive muscle weakness. In addition, PLEC mutations have been shown to lead to EBS-MD with myasthenic syndrome, EBS with pyloric atresia, or limb-girdle muscular dystrophy type (LGMDR17). The only dominant mutation identified in PLEC so far causes EBS-Ogna, a disease characterized by fragile skin without any muscular symptoms. With skeletal muscles harboring desmin-positive protein aggregates, degenerative changes of the myofibrillar apparatus, and mitochondrial abnormalities, most plectinopathies can be annotated among the expanding group of MFM. In skeletal muscle, the interplay between plectin and desmin IFs is essential for fiber integrity and cytoarchitecture. Accordingly, the loss of IF network function and the concomitant increased mechanical vulnerability of myofibers are supposed to be underlying mechanisms of MFMs. In her project, Dr. Winter aims to gain novel insights into the sequential steps that lead to cellular dysfunctions in various types of MDs. She wants to clarify the downstream molecular pathways and fundamental mechanisms that lead from myofiber alterations and resulting cellular stress to weakness and damage. By combining genetic, biochemical, cellular, molecular, and physiological approaches she tries to yield a more integrated picture of how skeletal muscle copes with stress under normal conditions and in disease. This will help to comprehend the sequential steps that lead to cellular dysfunctions in plectinopathies as well as in MFM, and clarify the molecular pathways that lead from aberrant IF arrangement and resulting cellular stress responses to weakness and damage.