Treadmill exercise reduces α-synuclein spreading via PPARα

Area of Science:

• Neuroscience
• Neurodegenerative Diseases
• Exercise Physiology

Background:

• Alpha-synuclein (α-syn) aggregation and spreading are hallmarks of neurodegenerative diseases like Parkinson's.
• Preformed fibril (PFF) seeding in A53T mice models accelerates α-syn pathology and dopaminergic neuron loss.
• The neuroprotective effects of exercise in α-synucleinopathies require further mechanistic elucidation.

Purpose of the Study:

• To investigate the impact of treadmill exercise on α-synuclein spreading and dopaminergic neuron survival in A53T mice.
• To elucidate the molecular mechanisms underlying exercise-induced neuroprotection, focusing on peroxisome proliferator-activated receptor alpha (PPARα) and TFEB.
• To assess the therapeutic potential of PPARα agonists in mitigating α-synucleinopathy.

Main Methods:

• Induction of α-synuclein pathology via PFF seeding in young A53T mice.
• Implementation of regular treadmill exercise protocols in young and aged A53T mice.
• Assessment of α-synuclein spreading, dopaminergic neuron loss, PPARα activation, TFEB-mediated lysosomal biogenesis, and the effects of fenofibrate (PPARα agonist).

Main Results:

• Treadmill exercise significantly decreased α-synuclein spreading and protected nigral dopaminergic neurons in PFF-seeded A53T mice.
• Exercise-induced neuroprotection was associated with increased brain PPARα activation, leading to enhanced lysosomal biogenesis via TFEB.
• Mice lacking PPARα did not show exercise-induced TFEB activation or α-synucleinopathy mitigation; fenofibrate treatment replicated exercise benefits.

Conclusions:

• Treadmill exercise confers significant neuroprotection against α-synuclein spreading and dopaminergic neuron loss in a mouse model of α-synucleinopathy.
• The beneficial effects of exercise are mediated through the PPARα-TFEB pathway, which stimulates lysosomal biogenesis.
• Targeting PPARα represents a promising therapeutic strategy for reducing α-synuclein pathology in neurodegenerative conditions.