Djavad Mowafaghian Centre for Brain Health and Division of Neurology, University of British Columbia, 2215 Wesbrook Mall, Vancouver, BC, Canada.
Acta Neuropathol Commun. 2021 Apr 1;9(1):57. doi: 10.1186/s40478-021-01158-x.
Frontotemporal lobar degeneration (FTLD) causes a spectrum of clinical presentations of frontotemporal dementia (FTD), including progressive changes in behavior, personality, executive function, and language. Up to 20% of familial FTLD cases are caused by progranulin (GRN) haploinsufficiency (FTD-GRN), with one of the most common causal variant being a nonsense mutation at arginine 493 (R493X). Recently, a genetic knockin FTD-GRN mouse model was generated bearing this Grn mutation, at the analogous arginine in murine Grn. Aged, homozygous Grn mice (Grn) have been shown to phenotypically replicate several neuropathological hallmarks previously demonstrated in Grn null mice. We conducted a comprehensive neuropathological and behavioral assessment of 18 month old Grn mice, observing a striking lysosomal dysfunction and thalamic neurodegeneration not previously described in this model, as well as a male-specific increase in generalized anxiety. These findings provide additional phenotypic markers of pathogenesis in aged Grn mice that will contribute to better defining mechanisms underlying FTD-GRN, and offer relevant outcome measures for preclinical efficacy testing of novel therapeutics that target nonsense mutations leading to this devastating disease.
额颞叶变性（FTLD）导致额颞痴呆（FTD）的一系列临床表现，包括行为、个性、执行功能和语言的进行性变化。多达 20%的家族性 FTLD 病例是由颗粒蛋白前体（GRN）单倍不足（FTD-GRN）引起的，最常见的致病变异之一是精氨酸 493（R493X）的无义突变。最近，一种具有这种 Grn 突变的遗传敲入 FTD-GRN 小鼠模型在鼠 Grn 中的类似精氨酸处被生成。已经证明，高龄纯合 Grn 小鼠（Grn）在表型上复制了先前在 Grn 缺失小鼠中证明的几种神经病理学特征。我们对 18 个月大的 Grn 小鼠进行了全面的神经病理学和行为评估，观察到以前在该模型中未描述的明显溶酶体功能障碍和丘脑神经退行性变，以及雄性特有的广泛性焦虑增加。这些发现为老年 Grn 小鼠的发病机制提供了额外的表型标志物，有助于更好地定义导致这种毁灭性疾病的 FTD-GRN 的机制，并为针对导致这种疾病的无义突变的新型治疗药物的临床前疗效测试提供相关的结果衡量标准。
