Filamin C myopathy: from pathogenic mutations towards novel targeted treatment concepts

细丝蛋白C相关的肌病描述了由FlnC基因突变引起的疾病。除了最初对人类FlnC突变的描述外，我们还对相关的肌肉病理特征和生化病理机制进行了全面的分析。拟议项目的第一个主要目标是更深入地了解FlnC突变的病理后果，并根据第一个资助期的结果测试治疗方法。为了解决这个问题，我们将在疾病参与的背景下对新发现的聚集成分和细丝蛋白C配体进行表征，并在丝氨酸病细胞培养模型中评估伴侣诱导剂对聚集形成的影响。这些研究将得到细胞一级信号通路研究的补充，重点是选择性自噬蛋白的降解。第二个主要目的是破译MFM中蛋白质聚集体的组成，以获得对病理机制的新见解。为了实现这一目标，我们将把我们在丝氨酸病中成功进行的蛋白质组分析扩展到其他基因明确的MFM亚型，并将结果与其他蛋白质聚集性肌病进行比较。

Filamin C-related myopathies delineate diseases caused by mutations in the FLNC gene. Beyond the first descriptions of human FLNC mutations, we have provided comprehensive analyses of associated myopathological characteristics and biochemical pathomechanisms. The first major goal of the proposed project is to obtain deeper insight into the pathological consequences of FLNC mutations and to test therapeutic approaches based on results of the first funding period. To address this issue we will characterize newly identified aggregate components and filamin C ligands in the context of their disease involvement and evaluate effects of chaperone-inducing agents on aggregate formation in cell culture models of filaminopathy. These studies will be complemented by investigations of signalling pathways at the cellular level, with an emphasis on selective autophagic protein degradation. The second main aim is to decipher the composition of protein aggregates in MFM to get new insights in pathomechanisms. To achieve this goal we will extend our proteomic analysis successfully performed in filaminopathy to additional genetically clarified MFM subtypes and compare the results with other protein aggregate myopathies.