Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, USA.
Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, USA.
Brain. 2020 Jun 1;143(6):1905-1919. doi: 10.1093/brain/awaa141.
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.
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大脑衰老有关。在额颞叶痴呆（FTD）中，高表达 TMEM106B 风险单倍型被证明会增加携带 TDP-43 包涵体的 FTD（FTD-TDP）的易感性，并修饰颗粒蛋白基因突变携带者的疾病外显率（FTD-GRN）。为了阐明 TMEM106B 的生物学功能，并确定降低 TMEM106B 是否可能成为一种可行的治疗策略，我们对我们最近开发的 Tmem106b-/- 小鼠模型中 8 个月大的动物进行了大脑转录组分析。我们包括 10 只 Tmem106b+/+（野生型）、10 只 Tmem106b+/-和 10 只 Tmem106b-/-小鼠。在 Tmem106b-/-和野生型动物之间，发现了 153 个下调基因和 60 个上调基因，这些基因富集在髓鞘形成相关的细胞过程中，包括轴突鞘和少突胶质细胞分化。共表达分析还表明，最下调的一组相关基因富集在髓鞘形成相关过程中。我们还检测到 Tmem106b-/-小鼠胼胝体中 OLIG2 阳性细胞的显著缺失，这种缺失在幼鼠（21 天）中已经存在，并持续到老年（23 个月），且没有恶化。定量聚合酶链反应显示，分化但未分化的少突胶质细胞细胞标记物减少。虽然在未受挑战的动物中，超微结构水平上没有观察到明显的髓鞘变化，但用 cuprizone 处理表明，Tmem106b-/-小鼠对 cuprizone 诱导的脱髓鞘更敏感，且髓鞘再生能力降低，这一发现我们在新生成的 Tmem106b CRISPR/cas9 敲除小鼠模型中得到了复制。最后，我们使用 TMEM106B HeLa 敲除细胞系和原代培养的少突胶质细胞，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，这可能对旨在降低 TMEM106B 水平的治疗策略产生影响。
