PDF(Pubmed)
Abstract：
The autophagy-lysosomal pathway plays a critical role in the clearance of tau protein aggregates that deposit in the brain in tauopathies, and defects in this system are associated with disease pathogenesis. Here, we report that expression of Tau35, a tauopathy-associated carboxy-terminal fragment of tau, leads to lipid accumulation in cell lines and primary cortical neurons. Our findings suggest that this is likely due to a deleterious block of autophagic clearance and lysosomal degradative capacity by Tau35. Notably, upon induction of autophagy by Torin 1, Tau35 inhibited nuclear translocation of transcription factor EB (TFEB), a key regulator of lysosomal biogenesis. Both cell lines and primary cortical neurons expressing Tau35 also exhibited changes in endosomal protein expression. These findings implicate autophagic and endolysosomal dysfunction as key pathological mechanisms through which disease-associated tau fragments could lead to the development and progression of tauopathy.
摘要：
自噬-溶酶体途径在Tau蛋白蛋白聚集物的清除中起关键作用，该系统的缺陷与疾病的发病机制有关。这里,我们报道了Tau35的表达，Tau蛋白与tau蛋白病相关的羧基末端片段，导致细胞系和原代皮质神经元中的脂质积累。我们的发现表明，这可能是由于Tau35对自噬清除和溶酶体降解能力的有害阻断。值得注意的是,在Torin1诱导自噬后，Tau35抑制转录因子EB（TFEB）的核易位，溶酶体生物发生的关键调节因子。表达Tau35的细胞系和原代皮质神经元也表现出内体蛋白表达的变化。这些发现暗示自噬和内溶酶体功能障碍是与疾病相关的tau片段可能导致tau蛋白病的发展和进展的关键病理机制。
