Treadmill exercise reduces α-synuclein spreading via PPARα

Cell Rep. 2022 Jul 12;40(2):111058. doi: 10.1016/j.celrep.2022.111058.

Abstract

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.

Keywords: CP: Neuroscience; PPARα; Parkinson’s disease; TFEB; dopamine; lysosomal function; treadmill; α-synuclein.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Disease Models, Animal
  • Dopaminergic Neurons / metabolism
  • Mice
  • PPAR alpha* / metabolism
  • Physical Conditioning, Animal* / physiology
  • Substantia Nigra / metabolism
  • Synucleinopathies*
  • alpha-Synuclein* / metabolism

Substances

  • PPAR alpha
  • alpha-Synuclein