The human genome expresses thousands of natural antisense transcripts (NAT) that can regulate epigenetic state, transcription, RNA stability or translation of their overlapping genes^1,2. Here we describe MAPT-AS1, a brain-enriched NAT that is conserved in primates and contains an embedded mammalian-wide interspersed repeat (MIR), which represses tau translation by competing for ribosomal RNA pairing with the MAPT mRNA internal ribosome entry site³. MAPT encodes tau, a neuronal intrinsically disordered protein (IDP) that stabilizes axonal microtubules. Hyperphosphorylated, aggregation-prone tau forms the hallmark inclusions of tauopathies⁴. Mutations in MAPT cause familial frontotemporal dementia, and common variations forming the MAPT H1 haplotype are a significant risk factor in many tauopathies⁵ and Parkinson’s disease. Notably, expression of MAPT-AS1 or minimal essential sequences from MAPT-AS1 (including MIR) reduces—whereas silencing MAPT-AS1 expression increases—neuronal tau levels, and correlate with tau pathology in human brain. Moreover, we identified many additional NATs with embedded MIRs (MIR-NATs), which are overrepresented at coding genes linked to neurodegeneration and/or encoding IDPs, and confirmed MIR-NAT-mediated translational control of one such gene, PLCG1. These results demonstrate a key role for MAPT-AS1 in tauopathies and reveal a potentially broad contribution of MIR-NATs to the tightly controlled translation of IDPs⁶, with particular relevance for proteostasis in neurodegeneration.

人类基因组表达数以千计的天然反义转录本 (NAT)，这些转录本可以调节其重叠基因的表观遗传状态、转录、RNA 稳定性或翻译^1,2。在这里，我们描述了 MAPT-AS1，一种大脑富集的 NAT，在灵长类动物中保守，包含嵌入的哺乳动物范围的散布重复序列 (MIR)，它通过与 MAPT mRNA内部核糖体进入位点³竞争核糖体 RNA 配对来抑制 tau 翻译。MAPT编码 tau，这是一种神经元固有紊乱蛋白 (IDP)，可稳定轴突微管。过度磷酸化、易于聚集的 tau 蛋白形成了 tau 蛋白病的标志性内含物⁴。MAPT突变会导致家族性额颞叶痴呆，而形成MAPT H1 单倍型的常见变异是许多 tau蛋白病⁵和帕金森病的重要危险因素。值得注意的是，MAPT-AS1 或 MAPT-AS1 的最小必需序列（包括 MIR）的表达会降低神经元 tau 水平，而沉默 MAPT-AS1 表达会增加神经元 tau 水平，并与人脑中的 tau 病理学相关。此外，我们还发现了许多其他带有嵌入式 MIR (MIR-NAT) 的 NAT，这些 NAT 在与神经变性和/或编码 IDP 相关的编码基因中过量表达，并证实了 MIR-NAT 介导的一种这样的基因PLCG1的翻译控制。这些结果证明了 MAPT-AS1 在 tau蛋白病中的关键作用，并揭示了 MIR-NAT 对 IDP 严格控制翻译的潜在广泛贡献⁶，特别与神经变性中的蛋白质稳态相关。