Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
J Neurosci. 2012 Aug 15;32(33):11213-27. doi: 10.1523/JNEUROSCI.0521-12.2012.
Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) is a fatal neurodegenerative disease with no available treatments. Mutations in the progranulin gene (GRN) causing impaired production or secretion of progranulin are a common Mendelian cause of FTLD-TDP; additionally, common variants at chromosome 7p21 in the uncharacterized gene TMEM106B were recently linked by genome-wide association to FTLD-TDP with and without GRN mutations. Here we show that TMEM106B is neuronally expressed in postmortem human brain tissue, and that expression levels are increased in FTLD-TDP brain. Furthermore, using an unbiased, microarray-based screen of >800 microRNAs (miRs), we identify microRNA-132 as the top microRNA differentiating FTLD-TDP and control brains, with <50% normal expression levels of three members of the microRNA-132 cluster (microRNA-132, microRNA-132*, and microRNA-212) in disease. Computational analyses, corroborated empirically, demonstrate that the top mRNA target of both microRNA-132 and microRNA-212 is TMEM106B; both microRNAs repress TMEM106B expression through shared microRNA-132/212 binding sites in the TMEM106B 3'UTR. Increasing TMEM106B expression to model disease results in enlargement and poor acidification of endo-lysosomes, as well as impairment of mannose-6-phosphate-receptor trafficking. Finally, endogenous neuronal TMEM106B colocalizes with progranulin in late endo-lysosomes, and TMEM106B overexpression increases intracellular levels of progranulin. Thus, TMEM106B is an FTLD-TDP risk gene, with microRNA-132/212 depression as an event which can lead to aberrant overexpression of TMEM106B, which in turn alters progranulin pathways. Evidence for this pathogenic cascade includes the striking convergence of two independent, genomic-scale screens on a microRNA:mRNA regulatory pair. Our findings open novel directions for elucidating miR-based therapies in FTLD-TDP.
额颞叶变性伴 TDP-43 包涵体（FTLD-TDP）是一种致命的神经退行性疾病，目前尚无有效治疗方法。颗粒蛋白前体（GRN）基因突变导致颗粒蛋白产生或分泌受损是 FTLD-TDP 的常见孟德尔病因；此外，染色体 7p21 上未明确的 TMEM106B 基因的常见变体最近通过全基因组关联与伴有和不伴有 GRN 突变的 FTLD-TDP 相关联。本文中，我们发现 TMEM106B 在死后人脑组织中有神经元表达，并且在 FTLD-TDP 脑中有表达增加。此外，我们使用 >800 个 microRNAs（miRs）的无偏、基于微阵列的筛选，鉴定出 microRNA-132 是区分 FTLD-TDP 和对照大脑的顶级 microRNA，疾病中三个 microRNA-132 簇成员（microRNA-132、microRNA-132*和 microRNA-212）的正常表达水平<50%。计算分析，经验证，表明 top mRNA 目标的 microRNA-132 和 microRNA-212 是 TMEM106B；两个 microRNAs 通过 TMEM106B 3'UTR 中的共享 microRNA-132/212 结合位点抑制 TMEM106B 表达。模拟疾病的 TMEM106B 表达增加导致内溶酶体增大和酸化不良，以及甘露糖-6-磷酸受体运输受损。最后，内源性神经元 TMEM106B 与晚期内溶酶体中的颗粒蛋白前体共定位，TMEM106B 过表达增加细胞内颗粒蛋白前体水平。因此，TMEM106B 是 FTLD-TDP 的风险基因，microRNA-132/212 下调是导致 TMEM106B 异常过表达的事件，进而改变颗粒蛋白途径。这一致病级联的证据包括两个独立的、基于全基因组的筛选在 microRNA:mRNA 调节对中的惊人收敛。我们的发现为阐明 FTLD-TDP 中的基于 miR 的治疗方法开辟了新的方向。
