Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195, USA.
Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA.
Brain. 2023 Aug 1;146(8):3206-3220. doi: 10.1093/brain/awad032.
Alzheimer's disease and related disorders feature neurofibrillary tangles and other neuropathological lesions composed of detergent-insoluble tau protein. In recent structural biology studies of tau proteinopathy, aggregated tau forms a distinct set of conformational variants specific to the different types of tauopathy disorders. However, the constituents driving the formation of distinct pathological tau conformations on pathway to tau-mediated neurodegeneration remain unknown. Previous work demonstrated RNA can serve as a driver of tau aggregation, and RNA associates with tau containing lesions, but tools for evaluating tau/RNA interactions remain limited. Here, we employed molecular interaction studies to measure the impact of tau/RNA binding on tau microtubule binding and aggregation. To investigate the importance of tau/RNA complexes (TRCs) in neurodegenerative disease, we raised a monoclonal antibody (TRC35) against aggregated tau/RNA complexes. We showed that native tau binds RNA with high affinity but low specificity, and tau binding to RNA competes with tau-mediated microtubule assembly functions. Tau/RNA interaction in vitro promotes the formation of higher molecular weight tau/RNA complexes, which represent an oligomeric tau species. Coexpression of tau and poly(A)45 RNA transgenes in Caenorhabditis elegans exacerbates tau-related phenotypes including neuronal dysfunction and pathological tau accumulation. TRC35 exhibits specificity for Alzheimer's disease-derived detergent-insoluble tau relative to soluble recombinant tau. Immunostaining with TRC35 labels a wide variety of pathological tau lesions in animal models of tauopathy, which are reduced in mice lacking the RNA binding protein MSUT2. TRC-positive lesions are evident in many human tauopathies including Alzheimer's disease, progressive supranuclear palsy, corticobasal degeneration and Pick's disease. We also identified ocular pharyngeal muscular dystrophy as a novel tauopathy disorder, where loss of function in the poly(A) RNA binding protein (PABPN1) causes accumulation of pathological tau in tissue from post-mortem human brain. Tau/RNA binding drives tau conformational change and aggregation inhibiting tau-mediated microtubule assembly. Our findings implicate cellular tau/RNA interactions as modulators of both normal tau function and pathological tau toxicity in tauopathy disorders and suggest feasibility for novel therapeutic approaches targeting TRCs.
阿尔茨海默病和相关疾病的特征是神经原纤维缠结和其他由去污剂不溶性 tau 蛋白组成的神经病理学病变。在最近的 tau 蛋白病变的结构生物学研究中，聚集的 tau 形成了一组独特的构象变体，这些变体特定于不同类型的 tau 病变疾病。然而，导致 tau 介导的神经退行性病变过程中形成不同的病理性 tau 构象的成分仍然未知。先前的工作表明 RNA 可以作为 tau 聚集的驱动因素，并且 RNA 与包含 tau 的病变相关，但评估 tau/RNA 相互作用的工具仍然有限。在这里，我们采用分子相互作用研究来测量 tau/RNA 结合对 tau 微管结合和聚集的影响。为了研究 tau/RNA 复合物 (TRC) 在神经退行性疾病中的重要性，我们针对聚集的 tau/RNA 复合物产生了单克隆抗体 (TRC35)。我们表明天然 tau 与 RNA 具有高亲和力但低特异性结合，并且 tau 与 RNA 的结合会与 tau 介导的微管组装功能竞争。体外 tau/RNA 相互作用促进形成更高分子量的 tau/RNA 复合物，这代表寡聚 tau 物种。在秀丽隐杆线虫中共同表达 tau 和 poly(A)45 RNA 转基因会加剧与 tau 相关的表型，包括神经元功能障碍和病理性 tau 积累。TRC35 对阿尔茨海默病衍生的去污剂不溶性 tau 相对于可溶性重组 tau 具有特异性。用 TRC35 免疫染色标记了 tau 病变动物模型中的各种病理性 tau 病变，在缺乏 RNA 结合蛋白 MSUT2 的小鼠中这些病变减少。TRC 阳性病变在包括阿尔茨海默病、进行性核上性麻痹、皮质基底节变性和皮克病在内的许多人类 tau 病变中都很明显。我们还确定了眼咽肌营养不良症为一种新的 tau 病变疾病，其中聚 (A) RNA 结合蛋白 (PABPN1) 的功能丧失导致死后人脑组织中病理性 tau 的积累。tau/RNA 结合驱动 tau 构象变化和聚集，抑制 tau 介导的微管组装。我们的发现表明细胞 tau/RNA 相互作用是 tau 病变疾病中正常 tau 功能和病理性 tau 毒性的调节剂，并表明针对 TRC 的新型治疗方法具有可行性。
