Pathological phosphorylated TDP-43 protein (pTDP) deposition drives neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP). However, the cellular and genetic mechanisms at work in pathological TDP-43 toxicity are not fully elucidated. To identify genetic modifiers of TDP-43 neurotoxicity, we utilized a Caenorhabditis elegans model of TDP-43 proteinopathy expressing human mutant TDP-43 pan-neuronally (TDP-43 tg). In TDP-43 tg C. elegans, we conducted a genome-wide RNAi screen covering 16,767 C. elegans genes for loss of function genetic suppressors of TDP-43-driven motor dysfunction. We identified 46 candidate genes that when knocked down partially ameliorate TDP-43 related phenotypes; 24 of these candidate genes have conserved homologs in the human genome. To rigorously validate the RNAi findings, we crossed the TDP-43 transgene into the background of homozygous strong genetic loss of function mutations. We have confirmed 9 of the 24 candidate genes significantly modulate TDP-43 transgenic phenotypes. Among the validated genes we focused on, one of the most consistent genetic modifier genes protecting against pTDP accumulation and motor deficits was the heparan sulfate-modifying enzyme hse-5, the C. elegans homolog of glucuronic acid epimerase (GLCE). We found that knockdown of human GLCE in cultured human cells protects against oxidative stress induced pTDP accumulation. Furthermore, expression of glucuronic acid epimerase is significantly decreased in the brains of FTLD-TDP cases relative to normal controls, demonstrating the potential disease relevance of the candidate genes identified. Taken together these findings nominate glucuronic acid epimerase as a novel candidate therapeutic target for TDP-43 proteinopathies including ALS and FTLD-TDP.

中文翻译：

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全基因组分析显示硫酸乙酰肝素表异构酶调节 TDP-43 蛋白病。

病理性磷酸化 TDP-43 蛋白 (pTDP) 沉积导致肌萎缩侧索硬化 (ALS) 和额颞叶变性 (FTLD-TDP) 中的神经变性。然而，在病理性 TDP-43 毒性中起作用的细胞和遗传机制尚未完全阐明。为了确定 TDP-43 神经毒性的遗传修饰物，我们利用了 TDP-43 蛋白病的秀丽隐杆线虫模型，该模型在泛神经元上表达了人类突变体 TDP-43 (TDP-43 tg)。在 TDP-43 tg C. elegans 中，我们进行了全基因组 RNAi 筛选，涵盖了 16,767 个 C. elegans 基因，用于 TDP-43 驱动的运动功能障碍的功能遗传抑制因子的丧失。我们确定了 46 个候选基因，当它们被敲低时，可以部分改善 TDP-43 相关表型；这些候选基因中有 24 个在人类基因组中具有保守的同源物。为了严格验证 RNAi 的发现，我们将 TDP-43 转基因杂交到纯合性强遗传功能丧失突变的背景中。我们已经确认 24 个候选基因中有 9 个显着调节 TDP-43 转基因表型。在我们关注的经过验证的基因中，防止 pTDP 积累和运动缺陷的最一致的遗传修饰基因之一是硫酸乙酰肝素修饰酶 hse-5，即葡萄糖醛酸差向异构酶 (GLCE) 的秀丽隐杆线虫同源物。我们发现在培养的人类细胞中敲除人类 GLCE 可以防止氧化应激诱导的 pTDP 积累。此外，与正常对照相比，FTLD-TDP 病例大脑中葡萄糖醛酸差向异构酶的表达显着降低，证明了所鉴定候选基因的潜在疾病相关性。