2012年9月26日 電 /生物谷BIOON/ --近日，由RUB大學Rudolf Andre Kley領(lǐng)導的一個國際研究小組在雜志Brain上發(fā)表研究論文,，在細絲蛋白肌病研究領(lǐng)域獲得了突破性進展,。研究人員發(fā)現(xiàn)對抗異常蛋白沉積的保護機制在細絲蛋白肌病患者內(nèi)不能正常工作。
研究著重于細絲蛋白C基因（FLNC）發(fā)生突變后時如何引起細絲蛋白肌病的，細絲蛋白肌病主要表現(xiàn)為肌肉逐漸無力以及行走能力的喪失,。肌纖維由肌原纖維組成,，其中的蛋白質(zhì)細絲Ç在肌纖維的發(fā)育和維持中起至關(guān)重要作用。
該研究中分析了細絲蛋白C基因突變導致的肌原纖維肌病的原因,，肌原纖維肌病主要是由肌原纖維分解,、細絲蛋白C突變和其他蛋白質(zhì)聚集，大量肌纖維中的肌原纖維崩解導致的,。
研究人員發(fā)現(xiàn),，細絲蛋白肌病患者蛋白的沉積通常干擾細胞內(nèi)蛋白質(zhì)降解。正常情況下,，細胞會產(chǎn)生熱休克蛋白,，促進蛋白質(zhì)沉淀的降解，并確保其他蛋白質(zhì)維持自己正確的三維結(jié)構(gòu),。
研究人員希望通過早期治療物質(zhì)如刺激熱休克蛋白生成或以其他影響蛋白質(zhì)降解的方式積極影響疾病過程,。為了研究這個過程，他們開發(fā)出一種細胞培養(yǎng)模型,，能夠在實驗室中開展相關(guān)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.
