We identified an autosomal dominant progranulin mutation carrier without symptoms of dementia in her lifetime (Reduced Penetrance Mutation Carrier, RedPenMC). This resistance to develop expected pathology presents a unique opportunity to interrogate neurodegenerative mechanisms. We performed multimodal single-nuclei analyses of post-mortem frontal cortex from RedPenMC, including transcriptomics and global levels of chromatin marks. RedPenMC had an increased ratio of GRN-expressing microglia, higher levels of activating histone mark H3k4me3 in microglia and lower levels of the repressive chromatin marks H3k9me1 and H3k9me3 in the frontal cortex than her affected mutation carrier son and evidence of higher protein levels of progranulin in both plasma and brain homogenates. Although the study is limited to one case, the results support that restoring brain progranulin levels may be sufficient to escape neurodegeneration and FTD. In addition to previously identified modifier genes, it is possible that epigenetic marks may contribute to the increased progranulin expression in cases of reduced penetrance. These findings may stimulate similar follow-up studies and new therapeutic approaches.

中文翻译：

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颗粒蛋白前额颞叶痴呆外显率降低的单细胞多模态分析

我们确定了一个常染色体显性遗传的颗粒蛋白前体突变携带者，在她的一生中没有痴呆症状（减少外显率突变携带者，RedPenMC）。这种对发展预期病理学的抵抗为研究神经退行性机制提供了独特的机会。我们对 RedPenMC 的死后额叶皮层进行了多模式单核分析，包括转录组学和染色质标记的全局水平。与受影响的突变携带者儿子相比，RedPenMC 的小胶质细胞表达 GRN 的比例增加，小胶质细胞中激活组蛋白标记 H3k4me3 的水平更高，额叶皮质中抑制性染色质标记 H3k9me1 和 H3k9me3 的水平更低，并且有证据表明颗粒蛋白前体蛋白水平更高血浆和脑匀浆。虽然这项研究仅限于一个案例，结果支持恢复大脑颗粒蛋白前体水平可能足以避免神经退行性变和 FTD。除了先前确定的修饰基因外，表观遗传标记可能有助于在外显率降低的情况下增加颗粒蛋白前体的表达。这些发现可能会刺激类似的后续研究和新的治疗方法。