Treadmill exercise reduces α-synuclein spreading via PPARα

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. [Display omitted] •Treadmill exercise mitigates α-synuclein spreading in the brain•Striatal dopamine is protected in a PFF-seeding model by treadmill exercise•PPARα is activated in neurons by treadmill exercise•Activation of PPARα lowers α-synucleinopathy Dutta et al. demonstrate that regular treadmill exercise is capable of decreasing α-synuclein spreading in the brain and protecting nigral dopaminergic neurons in mice. However, treadmill running does not reduce α-synucleinopathy in mice lacking peroxisome proliferator-activated receptor α (PPARα), highlighting a role of PPARα in the beneficial effect of treadmill running.