Policarpo Rafaela, Wolfs Leen, Martínez-Montero Saul, Vandermeulen Lina, Royaux Ines, Van Peer Gert, Mestdagh Pieter, De Strooper Bart, Sierksma Annerieke, d'Ydewalle Constantin
Neuroscience Discovery, Janssen Research & Development, Janssen Pharmaceutica, Beerse, Belgium.
Vlaams Instituut voor Biotechnologie-Katholieke Universiteit Leuven Center for Brain & Disease Research, Leuven, Belgium.
PLoS One. 2025 Jan 6;20(1):e0314973. doi: 10.1371/journal.pone.0314973. eCollection 2025.
The MAPT gene encodes Tau protein, a member of the large family of microtubule-associated proteins. Tau forms large insoluble aggregates that are toxic to neurons in several neurological disorders, and neurofibrillary Tau tangles represent a key pathological hallmark of Alzheimer's disease (AD) and other tauopathies. Lowering Tau expression levels constitutes a potential treatment for AD but the mechanisms that regulate Tau expression at the transcriptional or translational level are not well understood. Natural antisense transcripts (NATs) are a particular class of long non-coding RNAs (lncRNAs) that can regulate expression of their overlapping protein-coding genes at the epigenetic, transcriptional, or translational level. We and others identified a long non-coding RNA associated with the MAPT gene, named MAPT antisense 1 (MAPT-AS1). We confirmed that MAPT-AS1 is expressed in neurons in human post mortem brain tissue. To study the role of MAPT-AS1 on MAPT expression regulation, we modulated the expression of this lncRNA in human neuroblastoma cell lines and in human induced pluripotent stem cell (iPSC) derived neurons. In contrast to previous reports, we observed no changes on MAPT mRNA or Tau protein levels upon modulation of MAPT-AS1 levels in these cellular models. Our data suggest that MAPT-AS1 does not regulate Tau expression levels in human neurons in vitro. Thus, MAPT-AS1 does not represent a valuable therapeutic target to lower Tau expression in patients affected by tauopathies including AD.
微管相关蛋白tau（MAPT）基因编码tau蛋白，它是微管相关蛋白大家族的一员。在几种神经疾病中，tau会形成对神经元有毒性的大的不溶性聚集体，神经原纤维tau缠结是阿尔茨海默病（AD）和其他tau蛋白病的关键病理标志。降低tau的表达水平是治疗AD的一种潜在方法，但在转录或翻译水平上调节tau表达的机制尚不清楚。天然反义转录本（NATs）是一类特殊的长链非编码RNA（lncRNAs），可在表观遗传、转录或翻译水平上调节其重叠的蛋白质编码基因的表达。我们和其他人鉴定出一种与MAPT基因相关的长链非编码RNA，命名为MAPT反义1（MAPT-AS1）。我们证实MAPT-AS1在人类死后脑组织的神经元中表达。为了研究MAPT-AS1在MAPT表达调控中的作用，我们在人神经母细胞瘤细胞系和人诱导多能干细胞（iPSC）衍生的神经元中调节了这种lncRNA的表达。与之前的报道相反，在这些细胞模型中调节MAPT-AS1水平后，我们未观察到MAPT mRNA或tau蛋白水平的变化。我们的数据表明，MAPT-AS1在体外不调节人类神经元中的tau表达水平。因此，对于包括AD在内的tau蛋白病患者，MAPT-AS1不是降低tau表达的有价值治疗靶点。
