Rosiglitazone activation of PPARγ-dependent signaling is neuroprotective in mutant huntingtin expressing cells.

Abstract

Peroxisome proliferator-activated receptor gamma (PPARγ) is a crucial transcription factor for neuroprotection in several brain diseases. Using a mouse model of Huntington's Disease (HD), we recently showed that PPARγ not only played a major function in preventing HD, but also oral intake of a PPARγ agonist (thiazolidinedione, TZD) significantly reduced the formation of mutant Huntingtin (mHtt) aggregates in the brain (e.g., cortex and striatum). The molecular mechanisms by which PPARγ exerts its HD neuroprotective effects remain unresolved. We investigated whether the PPARγ agonist (rosiglitazone) mediates neuroprotection in the mHtt expressing neuroblastoma cell line (N2A). Here we show that rosiglitazone upregulated the endogenous expression of PPARγ, its downstream target genes (including PGC1α, NRF-1 and Tfam) and mitochondrial function in mHtt expressing N2A cells. Rosiglitazone treatment also significantly reduced mHtt aggregates that included ubiquitin (Ub) and heat shock factor 1 (HSF1), as assessed by a filter-retardation assay, and increased the levels of the functional ubiquitin-proteasome system (UPS), HSF1 and heat shock protein 27/70 (HSP27/70) in N2A cells. Moreover, rosiglitazone treatment normalized endoplasmic reticulum (ER) stress sensors Bip, CHOP and ASK1, and significantly increased N2A cell survival. Taken together, these findings unveil new insights into the mechanisms by which activation of PPARγ signaling protects against the HD-mediated neuronal impairment. Further, our data also support the concept that PPARγ may be a novel therapeutic target for treating HD.

• Authors: Ming-Chang Chiang, Yi-Chuan Cheng, Christopher J Nicol, Kuan-Hung Lin, Chia-Hui Yen, Shiang-Jiuun Chen, Rong-Nan Huang
• Journal: Experimental cell research (Exp Cell Res) Vol. 338 Issue 2 Pg. 183-93 (Nov 01 2015) ISSN: 1090-2422 [Electronic] United States
• PMID: 26362846 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• DNA-Binding Proteins
• Heat Shock Transcription Factors
• Heat-Shock Proteins
• Hsf1 protein, mouse
• Htt protein, mouse
• Huntingtin Protein
• Nerve Tissue Proteins
• Neuroprotective Agents
• Nuclear Proteins
• PPAR gamma
• Thiazolidinediones
• Transcription Factors
• Ubiquitin
• Rosiglitazone
• Proteasome Endopeptidase Complex

Topics

• Animals
• Brain (drug effects)
• Brain Neoplasms (drug therapy, genetics)
• Cell Line, Tumor
• Cell Survival (drug effects)
• DNA-Binding Proteins (genetics)
• Disease Models, Animal
• Endoplasmic Reticulum Stress (drug effects)
• Heat Shock Transcription Factors
• Heat-Shock Proteins (genetics)
• Huntingtin Protein
• Huntington Disease (genetics)
• Mice
• Mitochondria (drug effects)
• Nerve Tissue Proteins (genetics)
• Neuroblastoma (drug therapy, genetics)
• Neuroprotective Agents (pharmacology)
• Nuclear Proteins (genetics)
• PPAR gamma (genetics)
• Proteasome Endopeptidase Complex (genetics)
• Rosiglitazone
• Signal Transduction (drug effects)
• Thiazolidinediones (pharmacology)
• Transcription Factors (genetics)
• Ubiquitin (genetics)
• Up-Regulation (drug effects)