Department of Neurology, Neuromuscular Center Ruhrgebiet, University Hospital Bergmannsheil, Ruhr-University, Bochum, Germany.
Autophagy. 2013 Mar;9(3):422-3. doi: 10.4161/auto.22921. Epub 2012 Dec 13.
Myofibrillar myopathy caused by FLNC/filamin C mutations is characterized by disintegration of myofibrils and a massive formation of protein aggregates within skeletal muscle fibers. We performed immunofluorescence studies in skeletal muscle sections from filaminopathy patients to detect disturbances of protein quality control mechanisms. Our analyses revealed altered expression of chaperone proteins and components of proteasomal and autophagic degradation pathways in abnormal muscle fibers that harbor protein deposits but not in neighboring muscle fibers without pathological protein aggregation. These findings suggest a dysfunction of protein stabilizing and degrading mechanisms that leads to a pathological accumulation of protein aggregates in abnormal fibers. Accordingly, a pharmacological modulation of chaperone activity may be a promising therapeutic strategy to prevent protein aggregation and to reduce disease progression. Newly established filaminopathy cell culture models provide a suitable basis for testing such pharmacological approaches.
由 FLNC/细丝蛋白 C 突变引起的肌原纤维肌病的特征是肌原纤维崩解和骨骼肌纤维内大量蛋白质聚集体的形成。我们在细丝蛋白病患者的骨骼肌切片中进行免疫荧光研究，以检测蛋白质质量控制机制的紊乱。我们的分析表明，在含有蛋白质沉积物的异常肌纤维中，伴侣蛋白的表达发生改变，蛋白酶体和自噬降解途径的组成部分也发生改变，但在没有病理蛋白聚集的相邻肌纤维中则没有改变。这些发现表明，蛋白质稳定和降解机制的功能障碍导致异常纤维中病理性蛋白质聚集体的积累。因此，调节伴侣蛋白活性的药理学方法可能是预防蛋白质聚集和减少疾病进展的有前途的治疗策略。新建立的细丝蛋白病细胞培养模型为测试这种药理学方法提供了合适的基础。
