Protective effects of the telomerase protein TERT have been shown in neurons and brain. We previously demonstrated that TERT protein can accumulate in mitochondria of Alzheimer’s disease (AD) brains and protect from pathological tau in primary mouse neurons. This prompted us to employ telomerase activators in order to boost telomerase expression in a mouse model of Parkinson’s disease (PD) overexpressing human wild type α-synuclein. Our aim was to test whether increased Tert expression levels were able to ameliorate PD symptoms and to activate protein degradation.

We found increased Tert expression in brain for both activators which correlated with a substantial improvement of motor functions such as gait and motor coordination while telomere length in the analysed region was not changed. Interestingly, only one activator (TA-65) resulted in a decrease of reactive oxygen species from brain mitochondria. Importantly, we demonstrate that total, phosphorylated and aggregated α-synuclein were significantly decreased in the hippocampus and neocortex of activator-treated mice corresponding to enhanced markers of autophagy suggesting an improved degradation of toxic alpha-synuclein. We conclude that increased Tert expression caused by telomerase activators is associated with decreased α-synuclein protein levels either by activating autophagy or by preventing or delaying impairment of degradation mechanisms during disease progression. This encouraging preclinical data could be translated into novel therapeutic options for neurodegenerative disorders such as PD.

端粒酶蛋白 TERT 的保护作用已在神经元和大脑中显示出来。我们之前证明了 TERT 蛋白可以在阿尔茨海默病 (AD) 大脑的线粒体中积累，并保护原代小鼠神经元免受病理性 tau 的影响。这促使我们使用端粒酶激活剂来提高过度表达人类野生型 α-突触核蛋白的帕金森病 (PD) 小鼠模型中的端粒酶表达。我们的目的是测试增加的Tert表达水平是否能够改善 PD 症状并激活蛋白质降解。

我们发现两种激活剂在大脑中的Tert表达增加，这与运动功能（如步态和运动协调）的显着改善相关，而分析区域的端粒长度没有改变。有趣的是，只有一种激活剂（TA-65）导致脑线粒体中的活性氧减少。重要的是，我们证明活化剂处理的小鼠的海马和新皮质中总的、磷酸化和聚集的 α-突触核蛋白显着降低，这与增强的自噬标志物相对应，表明有毒 α-突触核蛋白的降解得到改善。我们的结论是增加了Tert端粒酶激活剂引起的表达与α-突触核蛋白水平降低有关，通过激活自噬或通过预防或延缓疾病进展过程中降解机制的损害。这一令人鼓舞的临床前数据可以转化为神经退行性疾病（如 PD）的新治疗选择。