Modulation of energy deficiency in Huntington's disease via activation of the peroxisome proliferator-activated receptor gamma.

Abstract

Huntington's disease (HD) is a neurodegenerative disease caused by the expansion of a CAG trinucleotide repeat in exon 1 of the huntingtin (HTT) gene. Here, we report that the transcript of the peroxisome proliferator-activated receptor-γ (PPARγ), a transcription factor that is critical for energy homeostasis, was markedly downregulated in multiple tissues of a mouse model (R6/2) of HD and in lymphocytes of HD patients. Therefore, downregulation of PPARγ seems to be a pathomechanism of HD. Chronic treatment of R6/2 mice with an agonist of PPARγ (thiazolidinedione, TZD) rescued progressive weight loss, motor deterioration, formation of mutant Htt aggregates, jeopardized global ubiquitination profiles, reduced expression of two neuroprotective proteins (brain-derived neurotrophic factor and Bcl-2) and shortened life span exhibited by these mice. By reducing HTT aggregates and, thus, ameliorating the recruitment of PPARγ into HTT aggregates, chronic TZD treatment also elevated the availability of the PPARγ protein and subsequently normalized the expression of two of its downstream genes (the glucose transporter type 4 and PPARγ coactivator-1 alpha genes). The protective effects described above appear to have been exerted, at least partially, via direct activation of PPARγ in the brain, as TZD was detected in the brains of mice treated with TZD and because a PPARγ agonist (rosiglitazone) protected striatal cells from mHTT-evoked energy deficiency and toxicity. We demonstrated that the systematic downregulation of PPARγ seems to play a critical role in the dysregulation of energy homeostasis observed in HD, and that PPARγ is a potential therapeutic target for this disease.

• Authors: Ming-Chang Chiang, Chiung-Mei Chen, Maw-Rong Lee, Hsiao-Wen Chen, Hui-Mei Chen, Yu-Shuo Wu, Cheng-Han Hung, Jheng-Jie Kang, Ching-Pang Chang, Chen Chang, Yih-Ru Wu, Yau-Sheng Tsai, Yijuang Chern
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 19 Issue 20 Pg. 4043-58 (Oct 15 2010) ISSN: 1460-2083 [Electronic] England
• PMID: 20668093 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Glucose Transporter Type 4
• PPAR gamma
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Ppargc1a protein, mouse
• Thiazolidinediones
• Trans-Activators
• Transcription Factors
• Rosiglitazone
• 2,4-thiazolidinedione

Topics

• Adipocytes (metabolism)
• Animals
• Brain (metabolism)
• Down-Regulation
• Energy Metabolism
• Gene Expression Regulation
• Glucose Transporter Type 4 (genetics)
• Humans
• Huntington Disease (genetics, metabolism, pathology)
• Liver (metabolism)
• Lymphocytes (metabolism)
• Mice
• PPAR gamma (agonists, deficiency, genetics, metabolism)
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Polymerase Chain Reaction
• Rosiglitazone
• Thiazolidinediones (administration & dosage, pharmacology)
• Trans-Activators (genetics)
• Transcription Factors