Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS.
Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS.
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用来识别典型酵母蛋白的算法预测，大约250种人类蛋白，包括几种与神经退行性疾病相关的RNA结合蛋白，都含有一个独特的类似蛋白的结构域(PrLD)，富含不带电荷的极性氨基酸和甘氨酸。RNA结合蛋白中的PrLD对于核糖核蛋白颗粒的组装是必不可少的。然而，人类PrLD功能与疾病之间的相互作用尚不清楚。在这里，我们定义了遗传性退行性变影响肌肉、脑、运动神经元和骨骼的家族中hnRNPA2/B1和hnRNPA1的PrLD的致病突变，以及一个家族性ALS病例。野生型hnRNPA2和hnRNPA1显示出一种内在的组装成自种纤维的倾向，这种倾向因疾病突变而加剧。事实上，致病突变增强了PrLD中的“空间拉链”基序，该基序加速了自种纤维的形成，从而使野生型hnRNP的种子聚合。重要的是，疾病突变促进hnRNPA2和hnRNPA1过度整合到应激颗粒中，并推动动物模型中细胞质内含物的形成，概括了人类的病理。因此，由PrLD中一个有效的突变‘空间拉链’基序引起的失调聚合可引发退行性疾病。与PrLDs相关的蛋白质必须被认为是肌肉、脑、运动神经元和骨骼的蛋白质病的启动和传播的候选蛋白。
Algorithms designed to identify canonical yeast prions predict that ~250 human proteins, including several RNA-binding proteins associated with neurodegenerative disease, harbor a distinctive prion-like domain (PrLD) enriched in uncharged polar amino acids and glycine. PrLDs in RNA-binding proteins are essential for the assembly of ribonucleoprotein granules. However, the interplay between human PrLD function and disease is not understood. Here, we define pathogenic mutations in PrLDs of hnRNPA2/B1 and hnRNPA1 in families with inherited degeneration affecting muscle, brain, motor neuron and bone, and a case of familial ALS. Wild-type hnRNPA2 and hnRNPA1 display an intrinsic tendency to assemble into self-seeding fibrils, which is exacerbated by the disease mutations. Indeed, the pathogenic mutations strengthen a ‘steric zipper’ motif in the PrLD, which accelerates formation of self-seeding fibrils that cross-seed polymerization of wild-type hnRNP. Importantly, the disease mutations promote excess incorporation of hnRNPA2 and hnRNPA1 into stress granules and drive the formation of cytoplasmic inclusions in animal models that recapitulate the human pathology. Thus, dysregulated polymerization caused by a potent mutant ‘steric zipper’ motif in a PrLD can initiate degenerative disease. Related proteins with PrLDs must be considered candidates for initiating and perhaps propagating proteinopathies of muscle, brain, motor neuron and bone.
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