| First Author | Chiang MC | Year | 2010 |
| Journal | Hum Mol Genet | Volume | 19 |
| Issue | 20 | Pages | 4043-58 |
| PubMed ID | 20668093 | Mgi Jnum | J:164450 |
| Mgi Id | MGI:4833909 | Doi | 10.1093/hmg/ddq322 |
| Citation | Chiang MC, et al. (2010) Modulation of energy deficiency in Huntington's disease via activation of the peroxisome proliferator-activated receptor gamma. Hum Mol Genet 19(20):4043-58 |
| abstractText | 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-gamma (PPARgamma), 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 PPARgamma seems to be a pathomechanism of HD. Chronic treatment of R6/2 mice with an agonist of PPARgamma (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 PPARgamma into HTT aggregates, chronic TZD treatment also elevated the availability of the PPARgamma protein and subsequently normalized the expression of two of its downstream genes (the glucose transporter type 4 and PPARgamma coactivator-1 alpha genes). The protective effects described above appear to have been exerted, at least partially, via direct activation of PPARgamma in the brain, as TZD was detected in the brains of mice treated with TZD and because a PPARgamma agonist (rosiglitazone) protected striatal cells from mHTT-evoked energy deficiency and toxicity. We demonstrated that the systematic downregulation of PPARgamma seems to play a critical role in the dysregulation of energy homeostasis observed in HD, and that PPARgamma is a potential therapeutic target for this disease. |
