PPARγ as a therapeutic target to rescue mitochondrial function in neurological disease

Abstract

There is increasing evidence for the involvement of mitochondrial dysfunction and oxidative stress in the pathogenesis of many of the major neurodegenerative and neuroinflammatory diseases, suggesting that mitochondrial and antioxidant pathways may represent potential novel therapeutic targets. Recent years have seen a rapidly growing interest in the use of therapeutic strategies that can limit the defects in, or even to restore, mitochondrial function while reducing free radical generation. The peroxisome proliferation-activated receptor gamma (PPARγ), a ligand-activated transcription factor, has a wide spectrum of biological functions, regulating mitochondrial function, mitochondrial turnover, energy metabolism, antioxidant defence and redox balance, immune responses and fatty acid oxidation. In this review, we explore the evidence for potential beneficial effects of PPARγ agonists in a number of neurological disorders, including Parkinson’s disease, Alzheimer’s disease, Amyotrophic lateral sclerosis and Huntington’s disease, ischaemia, autoimmune encephalomyelitis and neuropathic pain. We discuss the mechanisms underlying those beneficial effects in particular in relation to mitochondrial function, antioxidant defence, cell death and inflammation, and suggest that the PPARγ agonists show significant promise as therapeutic agents in otherwise intractable neurological disease.

A locked immunometabolic switch underlies TREM2 R47H loss of function in human iPSC‐derived microglia

“…We found that phosphorylation at serine 571 was significantly enhanced in TREM2 variant iPS‐Mg, suggesting that PGC‐1α activity is downregulated in TREM2 variant cells (Figure Bi,Bii). PGC‐1α is also a coactivator with the nuclear receptor and transcription factor PPARγ widely expressed in inflammatory cells such as microglia and macrophages as well as adipose tissue where it controls inflammation, lipid metabolism, and glucose homeostasis . Following 2‐DG treatment, we found increased PPARγ transcriptional activity in control iPS‐Mg but no increase in AD R47H het or NHD T66M hom iPS‐Mg (Figure C) despite the increase in cell stress pathways in AD R47H het iPS‐Mg.…”

Impact of diabetes in the Friedreich ataxia clinical outcome measures study

“…Five of the FACOMS participants with DM reported using incretin‐based therapy. Also, it has been proposed that peroxisome proliferator‐activated receptor‐gamma agonists such as TZDs could have neuroprotective effects in FA by promoting mitochondrial biogenesis and reducing mitochondrial oxidant burden 34. However, as noted, the risk of cardiac dysfunction with some TZDs is cause for caution 35.…”

Antagonizing peroxisome proliferator‐activated receptor γ facilitates M1‐to‐M2 shift of microglia by enhancing autophagy via the LKB1–AMPK signaling pathway

“…Growing evidence indicates that PPARγ agonists efficiently display neuroprotective properties in response to harmful insults, particularly neuroinflammation. Activation of PPARγ by troglitazone and pioglitazone reduces infarct volume by improving neurological function following middle cerebral artery occlusion in rats (Corona & Duchen, 2016; Culman, Zhao, Gohlke & Herdegen, 2007). Also, PPARγ activation by rosiglitazone imparts antidepressant‐ and anxiolytic‐like effects (Guo et al., 2017).…”