Genetic variants that define two distinct haplotypes at the TMEM106B locus have been implicated in multiple neurodegenerative diseases and in healthy brain ageing. In frontotemporal dementia (FTD), the high expressing TMEM106B risk haplotype was shown to increase susceptibility for FTD with TDP-43 inclusions (FTD-TDP) and to modify disease penetrance in progranulin mutation carriers (FTD-GRN). To elucidate the biological function of TMEM106B and determine whether lowering TMEM106B may be a viable therapeutic strategy, we performed brain transcriptomic analyses in 8-month-old animals from our recently developed Tmem106b^−/− mouse model. We included 10 Tmem106b^+/+ (wild-type), 10 Tmem106b^+/− and 10 Tmem106^−/− mice. The most differentially expressed genes (153 downregulated and 60 upregulated) were identified between Tmem106b^−/− and wild-type animals, with an enrichment for genes implicated in myelination-related cellular processes including axon ensheathment and oligodendrocyte differentiation. Co-expression analysis also revealed that the most downregulated group of correlated genes was enriched for myelination-related processes. We further detected a significant loss of OLIG2-positive cells in the corpus callosum of Tmem106b^−/− mice, which was present already in young animals (21 days) and persisted until old age (23 months), without worsening. Quantitative polymerase chain reaction revealed a reduction of differentiated but not undifferentiated oligodendrocytes cellular markers. While no obvious changes in myelin were observed at the ultrastructure levels in unchallenged animals, treatment with cuprizone revealed that Tmem106b^−/− mice are more susceptible to cuprizone-induced demyelination and have a reduced capacity to remyelinate, a finding which we were able to replicate in a newly generated Tmem106b CRISPR/cas9 knock-out mouse model. Finally, using a TMEM106B HeLa knock-out cell line and primary cultured oligodendrocytes, we determined that loss of TMEM106B leads to abnormalities in the distribution of lysosomes and PLP1. Together these findings reveal an important function for TMEM106B in myelination with possible consequences for therapeutic strategies aimed at lowering TMEM106B levels.

中文翻译：

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TMEM106B 缺失导致髓鞘形成缺陷：对额颞叶痴呆治疗策略的影响。


在TMEM106B基因座上定义两种不同单倍型的遗传变异与多种神经退行性疾病和健康的大脑老化有关。在额颞叶痴呆 (FTD) 中，高表达TMEM106B风险单倍型可增加 TDP-43 内含物 (FTD-TDP) 的 FTD 易感性，并改变颗粒体蛋白前体突变携带者 (FTD- GRN ) 的疾病外显率。为了阐明 TMEM106B 的生物学功能并确定降低 TMEM106B 是否可能是一种可行的治疗策略，我们对来自我们最近开发的Tmem106b ^−/−小鼠模型的 8 个月大动物进行了脑转录组分析。我们纳入了 10 只Tmem106b ^+/+ （野生型）、10 只Tmem106b ^+/-和 10 只Tmem106 ^−/−小鼠。在Tmem106b ^−/−和野生型动物之间鉴定出差异最大的基因（153 个下调和 60 个上调），其中涉及髓鞘形成相关细胞过程（包括轴突鞘和少突胶质细胞分化）的基因富集。共表达分析还表明，下调幅度最大的相关基因组在髓鞘形成相关过程中富集。我们进一步检测到Tmem106b ^−/−小鼠胼胝体中 OLIG2 阳性细胞显着减少，这种情况在幼龄动物（21 天）中就已经存在，并持续到老年（23 个月），且没有恶化。定量聚合酶链反应显示分化但未分化少突胶质细胞标记物减少。 虽然在未受攻击的动物的超微结构水平上没有观察到髓鞘质的明显变化，但用铜宗治疗表明， Tmem106b ^-/−小鼠更容易受到铜宗诱导的脱髓鞘作用，并且髓鞘再生能力降低，我们能够复制这一发现在新生成的Tmem106b CRISPR/cas9 敲除小鼠模型中。最后，使用 TMEM106B HeLa 敲除细胞系和原代培养的少突胶质细胞，我们确定 TMEM106B 的缺失会导致溶酶体和 PLP1 分布异常。这些发现共同揭示了 TMEM106B 在髓鞘形成中的重要功能，并可能对旨在降低 TMEM106B 水平的治疗策略产生影响。