Neurobiology of exercise in Parkinson's disease

Epidemiological, preclinical, and clinical studies increasingly support exercise as a potent neuroprotective and disease-modifying intervention in Parkinson's disease (PD). Preclinical studies, including toxin- and α-synuclein-based models, using voluntary, forced, and skilled exercise paradigms demonstrate preservation of nigrostriatal dopaminergic neurons, improved motor function, and activation of convergent pathways. Protective processes include upregulation of neurotrophic factors (BDNF, GDNF, VEGF and Irisin), enhanced mitochondrial biogenesis and oxidative resilience, reduced neuroinflammation, improved basal ganglia synaptic plasticity and increased lysosomal functions. Additional emerging mechanisms underlying exercise-induced neuroprotection involve vascular remodeling, pathways regulating cellular oxygen and hypoxia, modulation of the gut microbiome, and epigenetic reprogramming. Importantly, clinical studies mirror these preclinical findings, demonstrating improvements in motor symptoms, balance, fitness, and quality of life, along with functionally positive changes in exercise-responsive biomarkers such as BDNF, irisin, and glutathione. Collectively, these highlight exercise as a robust, multifaceted therapeutic strategy with significant implications for PD prevention and management. This review synthesizes findings from the past 5 years across preclinical models and patient studies to define how exercise reduces PD risk, slows symptom progression, and engages biological pathways relevant to neuroprotection and restoration.Lay abstractExercise, as a consistent lifestyle habit, is beneficial to overall health with cardiovascular and cognitive benefits; and also supports a better quality of life throughout aging. Exercise has been demonstrated to reduce the risk of developing Parkinsons's Disease as well as to delay the symptoms of PD. In this review we will report recent (2020-2025) preclinical and clinical studies that examine the mechanisms underlying exercise's neuroprotective benefit related to PD.