Panayiotou Elena, Fella Eleni, Papacharalambous Revekka, Malas Stavros, Saraiva Maria Joao, Kyriakides Theodoros
Clinic A, Neuropathology Department, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.
The Cyprus School of Molecular Medicine, Nicosia, Cyprus.
PLoS One. 2017 Apr 13;12(4):e0175767. doi: 10.1371/journal.pone.0175767. eCollection 2017.
ATTRV30M amyloid neuropathy is a lethal autosomal dominant sensorimotor and autonomic neuropathy, caused by deposition of amyloid fibrils composed of aberrant transthyretin (TTR). Ages of onset and penetrance exhibit great variability and genetic factors have been implicated. Complement activation co-localizes with amyloid deposits in amyloidotic neuropathy and is possibly involved in the kinetics of amyloidogenesis. A candidate gene approach has recently identified C1q polymorphisms to correlate with disease onset in a Cypriot cohort of patients with ATTRV30M amyloid neuropathy. In the current study we use a double transgenic mouse model of ATTRV30M amyloid neuropathy in which C1q is ablated to elucidate further a possible modifier role for C1q. Amyloid deposition is found to be increased by 60% in the absence of C1q. Significant up regulation is also recorded in apoptotic and cellular stress markers reflecting extracellular toxicity of pre-fibrillar and fibrillar TTR. Our data further indicate that in the absence of C1q there is marked reduction of macrophages in association with amyloid deposits and thus less effective phagocytosis of TTR.
ATTRV30M淀粉样变神经病是一种致命的常染色体显性感觉运动和自主神经病变，由异常转甲状腺素蛋白（TTR）组成的淀粉样纤维沉积引起。发病年龄和外显率表现出很大的变异性，并且涉及遗传因素。补体激活与淀粉样变神经病中的淀粉样沉积物共定位，并且可能参与淀粉样蛋白生成的动力学过程。最近，一种候选基因方法已确定C1q多态性与塞浦路斯ATTRV30M淀粉样变神经病患者队列中的疾病发作相关。在当前研究中，我们使用了ATTRV30M淀粉样变神经病的双转基因小鼠模型，其中C1q被敲除，以进一步阐明C1q可能的修饰作用。发现在没有C1q的情况下，淀粉样沉积增加了60%。在反映前纤维状和纤维状TTR细胞外毒性的凋亡和细胞应激标志物中也记录到显著上调。我们的数据进一步表明，在没有C1q的情况下，与淀粉样沉积物相关的巨噬细胞明显减少，因此对TTR的吞噬作用效率较低。
