Pathogenic variants in the UBQLN2 gene cause X-linked dominant amyotrophic lateral sclerosis and/or frontotemporal dementia characterised by ubiquilin 2 aggregates in neurons of the motor cortex, hippocampus, and spinal cord. However, ubiquilin 2 neuropathology is also seen in sporadic and familial amyotrophic lateral sclerosis and/or frontotemporal dementia cases not caused by UBQLN2 pathogenic variants, particularly C9orf72-linked cases. This makes the mechanistic role of mutant ubiquilin 2 protein and the value of ubiquilin 2 pathology for predicting genotype unclear. Here we examine a cohort of 44 genotypically diverse amyotrophic lateral sclerosis cases with or without frontotemporal dementia, including eight cases with UBQLN2 variants (resulting in p.S222G, p.P497H, p.P506S, p.T487I (two cases), and p.P497L (three cases)). Using multiplexed (5-label) fluorescent immunohistochemistry, we mapped the co-localisation of ubiquilin 2 with phosphorylated TDP-43, dipeptide repeat aggregates, and p62, in the hippocampus of controls (n = 6), or amyotrophic lateral sclerosis with or without frontotemporal dementia in sporadic (n = 20), unknown familial (n = 3), SOD1-linked (n = 1), FUS-linked (n = 1), C9orf72-linked (n = 5), and UBQLN2-linked (n = 8) cases. We differentiate between i) ubiquilin 2 aggregation together with phosphorylated TDP-43 or dipeptide repeat proteins, and ii) ubiquilin 2 self-aggregation promoted by UBQLN2 pathogenic variants that cause amyotrophic lateral sclerosis/and frontotemporal dementia. Overall, we describe a hippocampal protein aggregation signature that fully distinguishes mutant from wildtype ubiquilin 2 in amyotrophic lateral sclerosis with or without frontotemporal dementia, whereby mutant ubiquilin 2 is more prone than wildtype to aggregate independently of driving factors. This neuropathological signature can be used to assess the pathogenicity of UBQLN2 gene variants and to understand the mechanisms of UBQLN2-linked disease.

中文翻译：

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肌萎缩侧索硬化症和额颞叶痴呆中致病性 UBQLN2 的海马聚集特征

UBQLN2 基因的致病性变异可导致 X 连锁显性肌萎缩侧索硬化症和/或额颞叶痴呆，其特征是泛素 2 在运动皮层、海马和脊髓的神经元中聚集。然而，泛素 2 神经病理学也见于并非由 UBQLN2 致病变异引起的散发性和家族性肌萎缩侧索硬化症和/或额颞叶痴呆病例，特别是 C9orf72 相关病例。这使得突变泛素2蛋白的机制作用以及泛素2病理学对于预测基因型的价值尚不清楚。在这里，我们检查了 44 例基因型不同的肌萎缩侧索硬化症病例，伴有或不伴有额颞叶痴呆，其中 8 例具有 UBQLN2 变异（导致 p.S222G、p.P497H、p.P506S、p.T487I（两例）和 p.S222G、p.P497H、p.P506S、p.T487I（两例）和 p. .P497L（三例））。使用多重（5 标记）荧光免疫组织化学，我们绘制了对照 (n = 6) 或伴有或不伴有肌萎缩侧索硬化症的海马中泛素 2 与磷酸化 TDP-43、二肽重复聚集体和 p62 的共定位额颞叶痴呆有散发性 (n = 20)、未知家族性 (n = 3)、SOD1 相关 (n = 1)、FUS 相关 (n = 1)、C9orf72 相关 (n = 5) 和 UBQLN2 相关 ( n = 8) 例。我们区分 i) 泛素 2 与磷酸化 TDP-43 或二肽重复蛋白的聚集，以及 ii) UBQLN2 致病性变异促进的泛素 2 自身聚集，导致肌萎缩侧索硬化症/和额颞叶痴呆。总体而言，我们描述了一种海马蛋白聚集特征，该特征在伴有或不伴有额颞叶痴呆的肌萎缩侧索硬化症中完全区分突变型和野生型泛素 2，其中突变型泛素 2 比野生型更容易独立于驱动因素聚集。这种神经病理学特征可用于评估 UBQLN2 基因变异的致病性并了解 UBQLN2 相关疾病的机制。