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

Abstract

Parkinson’s disease (PD) is the most common α-synucleinopathy worldwide. The pathognomonic hallmark of PD is the misfolding and propagation of the α-synuclein (α-syn) protein, observed in post-mortem histopathology. It has been hypothesized that α-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 α-synucleinopathy. Growing evidence suggests that peroxisome proliferator-activated receptor (PPAR) agonists confer neuroprotective effects in PD, however, whether they also confer an anti-α-synucleinopathy effect is unknown. Here we analyze the reported therapeutic effects of PPARs, specifically the gamma isoform (PPARγ), in preclinical PD animal models and clinical trials for PD, and we suggest possible anti-α-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.

Alterations in Blood Methylome as Potential Epigenetic Biomarker in Sporadic Parkinson's Disease

“…Moreover, we detected hypermethylation of the ACOT1 gene that plays a role in brain metabolism of long‐chain acyl‐CoAs 35 and is believed to be involved in PPAR regulation 36 . The interest in PPAR agonists as potential disease‐modifying agents for PD adds to the relevance of this epigenetic finding 37,38 . Additionally, we also found several hypermethylated genes associated with the NDRG4 gene; the protein encoded by this gene contributes to the maintenance of intracerebral BDNF levels and is required for cell cycle progression and survival of astrocytes.…”

“…36 The interest in PPAR agonists as potential diseasemodifying agents for PD adds to the relevance of this epigenetic finding. 37,38 Additionally, we also found several hypermethylated genes associated with the NDRG4 gene; the protein encoded by this gene contributes to the maintenance of intracerebral BDNF levels and is required for cell cycle progression and survival of astrocytes. This gene has been found to have reduced expression in the substantia nigra and cingulate gyrus of patients with PD.…”

Nuclear Receptors in Health and Diseases

“…Therefore, targeting proline metabolism and the PRODH/POX-PPARγ axis could be a potential new approach for treating breast cancer [19]. Lsaac et al investigated the therapeutic effects of PPARs, particularly the gamma isoform (PPARγ), in preclinical animal models of Parkinson's disease (PD) and clinical trials for PD [20]. They suggested the possible anti-α-synucleinopathy mechanisms downstream from these NRs [20].…”

“…Lsaac et al investigated the therapeutic effects of PPARs, particularly the gamma isoform (PPARγ), in preclinical animal models of Parkinson's disease (PD) and clinical trials for PD [20]. They suggested the possible anti-α-synucleinopathy mechanisms downstream from these NRs [20]. Understanding the neuroprotective mechanisms of PPARs, using preclinical models that mimic PD as closely as possible, can facilitate better clinical trials for disease-modifying medications in PD [20].…”

“…They suggested the possible anti-α-synucleinopathy mechanisms downstream from these NRs [20]. Understanding the neuroprotective mechanisms of PPARs, using preclinical models that mimic PD as closely as possible, can facilitate better clinical trials for disease-modifying medications in PD [20]. Fenofibrate, a widely used cholesterol-lowering agent, acts as a ligand of PPARα [21].…”