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Lilli Winter

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Research Focus
Protein aggregate myopathies (PAM) are progressive and devastating diseases of the human skeletal muscle that often lead to premature death. Although PAM share common features, they are associated with marked clinical variability and diagnosis is not always easy. PAM are defined by the presence of protein aggregates in muscle cells and therefore encompass a wide group of muscle disorders including myofibrillar myopathies (MFM), the largest group of PAM, and many other disorders such as actin filament aggregate myopathy, myosin storage myopathy, core myopathies, nemaline myopathies etc. (Olivé et al. 2021). Within the last years, great efforts have been undertaken to identify PAM-causing gene defects, describe PAM subtypes, and contribute to the understanding of clinical, genetic and pathophysiological aspects of these diseases. However, we are still far from understanding the molecular mechanisms leading from an individual gene defect to a mutually shared myopathological disease manifestation. Our knowledge of proteins and mechanisms involved (especially beyond aggregate formation) is limited, but critical for the understanding of patients’ needs and the development of treatment concepts.

Main Objectives
Our aim is to provide novel insights into the sequential steps that lead to cellular dysfunctions in various types of PAM, with a special focus on plectin- and desmin-related MFM, and to clarify the downstream molecular pathways and fundamental mechanisms that lead from myofiber alterations and resulting cellular stress to weakness and damage. Moreover, specific targeting of mutation-triggered aberrant cellular pathways has a high potential to provide compensation for the detrimental effects of mutations in PAM-associated proteins, laying the basis for future therapeutic approaches.

Content of Research
Focusing on the analysis of pathological molecular pathways (and their reversal) in PAM-related cell and animal models, we are using a multi-disciplinary approach by combining cell biological, molecular, biochemical, and biophysical methods. To investigate the highly complex disease pattern of plectin- and desmin-associated MFM, we use muscle-specific conditional plectin knockout (MCK-Cre/cKO) mice, plectin isoform-specific knockout mice, just lacking one specific plectin isoform (either plectin 1, 1b, or 1d) while expressing all others, as well as desmin knockout mice. We also evaluate patient-derived cell and tissue samples.