2012年9月26日 电 /生物谷BIOON/ --近日，由RUB大学Rudolf Andre Kley领导的一个国际研究小组在杂志Brain上发表研究论文，在细丝蛋白肌病研究领域获得了突破性进展。研究人员发现对抗异常蛋白沉积的保护机制在细丝蛋白肌病患者内不能正常工作。
研究着重于细丝蛋白C基因（FLNC）发生突变后时如何引起细丝蛋白肌病的，细丝蛋白肌病主要表现为肌肉逐渐无力以及行走能力的丧失。肌纤维由肌原纤维组成，其中的蛋白质细丝Ç在肌纤维的发育和维持中起至关重要作用。
该研究中分析了细丝蛋白C基因突变导致的肌原纤维肌病的原因，肌原纤维肌病主要是由肌原纤维分解、细丝蛋白C突变和其他蛋白质聚集，大量肌纤维中的肌原纤维崩解导致的。
研究人员发现，细丝蛋白肌病患者蛋白的沉积通常干扰细胞内蛋白质降解。正常情况下，细胞会产生热休克蛋白，促进蛋白质沉淀的降解，并确保其他蛋白质维持自己正确的三维结构。
研究人员希望通过早期治疗物质如刺激热休克蛋白生成或以其他影响蛋白质降解的方式积极影响疾病过程。为了研究这个过程，他们开发出一种细胞培养模型，能够在实验室中开展相关研究。（生物谷：Bioon.com）
doi:10.1093/brain/aws200
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Pathophysiology of protein aggregation and extended phenotyping in filaminopathy
Rudolf A. Kley*, Piraye Serdaroglu-Oflazer*, Yvonne Leber*, Zagaa Odgerel, Peter F. M. van der Ven, et al.
Mutations in FLNC cause two distinct types of myopathy. Disease associated with mutations in filamin C rod domain leading to expression of a toxic protein presents with progressive proximal muscle weakness and shows focal destructive lesions of polymorphous aggregates containing desmin, myotilin and other proteins in the affected myofibres; these features correspond to the profile of myofibrillar myopathy. The second variant associated with mutations in the actin-binding domain of filamin C is characterized by weakness of distal muscles and morphologically by non-specific myopathic features. A frameshift mutation in the filamin C rod domain causing haploinsufficiency was also found responsible for distal myopathy with some myofibrillar changes but no protein aggregation typical of myofibrillar myopathies. Controversial data accumulating in the literature require re-evaluation and comparative analysis of phenotypes associated with the position of the FLNC mutation and investigation of the underlying disease mechanisms. This is relevant and necessary for the refinement of diagnostic criteria and developing therapeutic approaches. We identified a p.W2710X mutation in families originating from ethnically diverse populations and re-evaluated a family with a p.V930_T933del mutation. Analysis of the expanded database allows us to refine clinical and myopathological characteristics of myofibrillar myopathy caused by mutations in the rod domain of filamin C. Biophysical and biochemical studies indicate that certain pathogenic mutations in FLNC cause protein misfolding, which triggers aggregation of the mutant filamin C protein and subsequently involves several other proteins. Immunofluorescence analyses using markers for the ubiquitin–proteasome system and autophagy reveal that the affected muscle fibres react to protein aggregate formation with a highly increased expression of chaperones and proteins involved in proteasomal protein degradation and autophagy. However, there is a noticeably diminished efficiency of both the ubiquitin–proteasome system and autophagy that impairs the muscle capacity to prevent the formation or mediate the degradation of aggregates. Transfection studies of cultured muscle cells imitate events observed in the patient’s affected muscle and therefore provide a helpful model for testing future therapeutic strategies.
