Centre for MND Research, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia.
Neurodegener Dis. 2017;17(6):304-312. doi: 10.1159/000481258. Epub 2017 Nov 11.
Mutations in the genes encoding the heterogeneous nuclear ribonucleoproteins hnRNPA1 and hnRNPA2/B1 have been reported in a multisystem proteinopathy that includes amyotrophic lateral sclerosis (ALS) and inclusion body myopathy associated with Paget disease of the bone and frontotemporal dementia. Mutations were also described in the prion-like domain of hnRNPA1 in patients with classic ALS. Another hnRNP protein, hnRNPA3, has been found to be associated with the ALS/frontotemporal dementia protein C9orf72.
To further assess their role in ALS, we examined these hnRNPs in spinal cord tissue from sporadic (SALS) and familial ALS (FALS) patients, including C9orf72 repeat expansion-positive patients, and controls. We also sought to determine the prevalence of HNRNPA1, HNRNPA2B1, and HNRNPA3 mutations in Australian ALS patients.
Immunostaining was used to assess hnRNPs in ALS patient spinal cords. Mutation analysis of the HNRNPA1, HNRNPA2B1, and HNRNPA3 genes was performed in FALS and of their prion-like domains in SALS patients.
Immunostaining of spinal motor neurons of ALS patients with the C9orf72 repeat expansion showed significant mislocalisation of hnRNPA3, and no differences in hnRNPA1 or A2/B1 localisation, compared to controls. No novel or known mutations were identified in HNRNPA1, HNRNPA2B1, or HNRNPA3 in Australian ALS patients.
hnRNPA3 pathology was identified in motor neurons of ALS patients with C9orf72 repeat expansions, implicating hnRNPA3 in the pathogenesis of C9orf72-linked ALS. hnRNPA3 warrants further investigation into the pathogenesis of ALS linked to C9orf72. This study also determined that HNRNP mutations are not a common cause of FALS and SALS in Australia.
编码异质核核糖核蛋白 hnRNPA1 和 hnRNPA2/B1 的基因突变已在一种多系统蛋白病中报道，该疾病包括肌萎缩侧索硬化症（ALS）和伴有骨 Pagets 病和额颞叶痴呆的包涵体肌病。在经典 ALS 患者的 PrP 样结构域中也描述了 hnRNPA1 突变。另一种 hnRNP 蛋白 hnRNPA3 与 ALS/额颞叶痴呆蛋白 C9orf72 相关。
为了进一步评估它们在 ALS 中的作用，我们检查了散发性（SALS）和家族性 ALS（FALS）患者脊髓组织中的这些 hnRNP，包括 C9orf72 重复扩展阳性患者和对照。我们还试图确定澳大利亚 ALS 患者中 HNRNPA1、HNRNPA2B1 和 HNRNPA3 突变的患病率。
免疫染色用于评估 ALS 患者脊髓中的 hnRNP。在 FALS 中对 HNRNPA1、HNRNPA2B1 和 HNRNPA3 基因进行突变分析，在 SALS 患者中对其 PrP 样结构域进行突变分析。
与对照组相比，C9orf72 重复扩展的 ALS 患者脊髓运动神经元的免疫染色显示 hnRNPA3 明显定位异常，而 hnRNPA1 或 A2/B1 定位无差异。在澳大利亚 ALS 患者中未发现 HNRNPA1、HNRNPA2B1 或 HNRNPA3 的新或已知突变。
在 C9orf72 重复扩展的 ALS 患者的运动神经元中发现了 hnRNPA3 病理学，提示 hnRNPA3 参与了 C9orf72 相关 ALS 的发病机制。hnRNPA3 值得进一步研究 C9orf72 相关 ALS 的发病机制。本研究还确定了 HNRNP 突变不是澳大利亚 FALS 和 SALS 的常见原因。
