Loss of TMEM106B leads to myelination deficits: implications for frontotemporal dementia treatment strategies

作者：Xiaolai Zhou, Alexandra M. Nicholson, Yingxue Ren, Mieu Brooks, Peizhou Jiang, Aamir Zuberi, Hung Nguyen Phuoc, Ralph B. Perkerson, Billie J. Matchett, Tammee M. Parsons, NiCole A. Finch, Wen-Lang Lin, Wenhui Qiao, Monica Castanedes‐Casey, Virginia Phillips, Ariston L Librero, Yan W. Asmann, Guojun Bu, Melissa E. Murray, Cathleen Lutz, Dennis W. Dickson, Rosa Rademakers · 发表于：Brain · 年份：2020 · DOI：10.1093/brain/awaa141 · 被引用次数：80 · 研究领域：Amyotrophic Lateral Sclerosis Research、Neuroinflammation and Neurodegeneration Mechanisms、Alzheimer's disease research and treatments

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 marke...