Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY, USA.
Nat Commun. 2021 Apr 14;12(1):2238. doi: 10.1038/s41467-021-22501-9.
Disrupted homeostasis of the microtubule binding protein tau is a shared feature of a set of neurodegenerative disorders known as tauopathies. Acetylation of soluble tau is an early pathological event in neurodegeneration. In this work, we find that a large fraction of neuronal tau is degraded by chaperone-mediated autophagy (CMA) whereas, upon acetylation, tau is preferentially degraded by macroautophagy and endosomal microautophagy. Rerouting of acetylated tau to these other autophagic pathways originates, in part, from the inhibitory effect that acetylated tau exerts on CMA and results in its extracellular release. In fact, experimental blockage of CMA enhances cell-to-cell propagation of pathogenic tau in a mouse model of tauopathy. Furthermore, analysis of lysosomes isolated from brains of patients with tauopathies demonstrates similar molecular mechanisms leading to CMA dysfunction. This study reveals that CMA failure in tauopathy brains alters tau homeostasis and could contribute to aggravate disease progression.
微管结合蛋白 tau 的平衡失调是一组称为 tau 病的神经退行性疾病的共同特征。可溶性 tau 的乙酰化是神经变性的早期病理事件。在这项工作中，我们发现大量神经元 tau 通过伴侣介导的自噬 (CMA) 降解，而在乙酰化后，tau 优先通过巨自噬和内体微自噬降解。乙酰化 tau 重新定向到这些其他自噬途径的部分原因来自乙酰化 tau 对 CMA 的抑制作用，并导致其细胞外释放。事实上，实验阻断 CMA 会增强 tau 病小鼠模型中致病性 tau 的细胞间传播。此外，对来自 tau 病患者大脑的溶酶体的分析表明，导致 CMA 功能障碍的类似分子机制。这项研究表明，tau 病大脑中的 CMA 失败会改变 tau 的平衡，并可能导致疾病进展恶化。
