Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA.
Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA; Division of Research and Development, Jesse Brown Veterans Affairs Medical Center, Chicago, IL, USA.
Cell Rep. 2022 Jul 12;40(2):111058. doi: 10.1016/j.celrep.2022.111058.
This study underlines the importance of treadmill exercise in reducing α-synuclein (α-syn) spreading in the A53T brain and protecting nigral dopaminergic neurons. Preformed α-syn fibril (PFF) seeding in the internal capsule of young A53T α-syn mice leads to increased spreading of α-syn to substantia nigra and motor cortex and concomitant loss of nigral dopaminergic neurons. However, regular treadmill exercise decreases α-syn spreading in the brain and protects nigral dopaminergic neurons in PFF-seeded mice. Accordingly, treadmill exercise also mitigates α-synucleinopathy in aged A53T mice. While investigating this mechanism, we have observed that treadmill exercise induces the activation of peroxisome proliferator-activated receptor α (PPARα) in the brain to stimulate lysosomal biogenesis via TFEB. Accordingly, treadmill exercise remains unable to stimulate TFEB and reduce α-synucleinopathy in A53T mice lacking PPARα, and fenofibrate, a prototype PPARα agonist, reduces α-synucleinopathy. These results delineate a beneficial function of treadmill exercise in reducing α-syn spreading in the brain via PPARα.
这项研究强调了跑步机运动在减少 α-突触核蛋白（α-syn）在 A53T 大脑中的传播和保护黑质多巴胺能神经元方面的重要性。在年轻的 A53T α-syn 小鼠的内囊中预先形成的 α-syn 纤维（PFF）接种会导致 α-syn 向黑质和运动皮层的传播增加，并伴有黑质多巴胺能神经元的丧失。然而，定期进行跑步机运动可以减少大脑中 α-syn 的传播，并保护 PFF 接种小鼠的黑质多巴胺能神经元。因此，跑步机运动也可以减轻老年 A53T 小鼠的 α-突触核蛋白病。在研究这一机制时，我们观察到跑步机运动诱导大脑中过氧化物酶体增殖物激活受体 α（PPARα）的激活，通过 TFEB 刺激溶酶体生物发生。因此，在缺乏 PPARα 的 A53T 小鼠中，跑步机运动仍然无法刺激 TFEB 并减少 α-突触核蛋白病，而作为 PPARα 激动剂的非诺贝特则可以减少 α-突触核蛋白病。这些结果描绘了跑步机运动通过 PPARα 减少大脑中 α-syn 传播的有益功能。
