PPARs and Their Neuroprotective Effects in Parkinson's Disease: A Novel Therapeutic Approach in α-Synucleinopathy?

Parkinson's disease (PD) is the most common alpha-synucleinopathy worldwide. The pathognomonic hallmark of PD is the misfolding and propagation of the alpha-synuclein (alpha-syn) protein, observed in post-mortem histopathology. It has been hypothesized that alpha-synucleinopathy triggers oxidative stress, mitochondrial dysfunction, neuroinflammation, and synaptic dysfunction, leading to neurodegeneration. To this date, there are no disease-modifying drugs that generate neuroprotection against these neuropathological events and especially against alpha-synucleinopathy. Growing evidence suggests that peroxisome proliferator-activated receptor (PPAR) agonists confer neuroprotective effects in PD, however, whether they also confer an anti-alpha-synucleinopathy effect is unknown. Here we analyze the reported therapeutic effects of PPARs, specifically the gamma isoform (PPAR gamma), in preclinical PD animal models and clinical trials for PD, and we suggest possible anti-alpha-synucleinopathy mechanisms acting downstream from these receptors. Elucidating the neuroprotective mechanisms of PPARs through preclinical models that mimic PD as closely as possible will facilitate the execution of better clinical trials for disease-modifying drugs in PD.