Neuroscience Research Australia, Randwick, Sydney, New South Wales, Australia.
Ann Neurol. 2010 Nov;68(5):639-49. doi: 10.1002/ana.22274.
Frontotemporal lobar degeneration (FTLD) is the most common cause of early-onset dementia. Pathological ubiquitinated inclusion bodies observed in FTLD and motor neuron disease (MND) comprise trans-activating response element (TAR) DNA binding protein (TDP-43) and/or fused in sarcoma (FUS) protein. Our objective was to identify the causative gene in an FTLD-MND pedigree with no mutations in known dementia genes.
A mutation screen of candidate genes, luciferase assays, and quantitative polymerase chain reaction (PCR) was performed to identify the biological role of the putative mutation. Neuropathological characterization of affected individuals and western blot studies of cell lines were performed to identify the pathological mechanism of the mutation.
We identified a nonpolymorphic mutation (c.67251G>T) in the 3'-untranslated region (UTR) of the Sigma nonopioid intracellular receptor 1 (SIGMAR1) gene in affected individuals from the FTLD-MND pedigree. The c.67251G>T mutation increased gene expression by 1.4-fold, corresponding with a significant 1.5-fold to 2-fold change in the SIGMAR1 transcript or Sigma-1 protein in lymphocyte or brain tissue. Brains of SIGMAR1 mutation carriers displayed a unique pathology with cytoplasmic inclusions immunopositive for either TDP-43 or FUS but not Sigma-1. Overexpression of SIGMAR1 shunted TDP-43 and FUS from the nucleus to the cytoplasm by 2.3-fold and 5.2-fold, respectively. Treatment of cells with Sigma-1 ligands significantly altered translocation of TDP-43 by up to 2-fold.
SIGMAR1 is a causative gene for familial FTLD-MND with a unique neuropathology that differs from other FTLD and MND cases. Our findings also suggest Sigma-1 drugs as potential treatments for the TDP-43/FUS proteinopathies.
额颞叶变性（FTLD）是早发性痴呆的最常见原因。在 FTLD 和运动神经元病（MND）中观察到的病理性泛素化包涵体包含反式激活反应元件（TAR）DNA 结合蛋白（TDP-43）和/或融合肉瘤（FUS）蛋白。我们的目的是在没有已知痴呆基因突变的 FTLD-MND 家系中鉴定致病基因。
对候选基因进行突变筛查、荧光素酶测定和定量聚合酶链反应（PCR），以确定假定突变的生物学作用。对受影响个体进行神经病理学特征分析，并对细胞系进行 Western blot 研究，以确定突变的病理机制。
我们在 FTLD-MND 家系中受影响个体中鉴定出 Sigma 非阿片类细胞内受体 1（SIGMAR1）基因 3'-非翻译区（UTR）中的非多态性突变（c.67251G>T）。c.67251G>T 突变使基因表达增加 1.4 倍，相应地，淋巴细胞或脑组织中 SIGMAR1 转录物或 Sigma-1 蛋白的变化为 1.5 至 2 倍。SIGMAR1 突变携带者的大脑显示出独特的病理学，细胞质包涵体免疫阳性，TDP-43 或 FUS，但不是 Sigma-1。SIGMAR1 的过表达使 TDP-43 和 FUS 分别从核内转位到细胞质中 2.3 倍和 5.2 倍。用 Sigma-1 配体处理细胞可使 TDP-43 的易位增加高达 2 倍。
SIGMAR1 是家族性 FTLD-MND 的致病基因，具有独特的神经病理学特征，与其他 FTLD 和 MND 病例不同。我们的发现还表明 Sigma-1 药物可能是 TDP-43/FUS 蛋白病的潜在治疗方法。
