title: PPARgamma rescue of the mitochondrial dysfunction in Huntington's disease.
abstract: Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a CAG trinucleotide expansion in the Huntingtin (Htt) gene. The resultant mutant Htt protein (mHtt) forms aggregates in the brain (e.g., cortex and striatum), and causes devastating neuronal degeneration. Transcriptional dysfunction caused by mHtt is critical for HD. We recently demonstrated that a crucial transcription factor peroxisome proliferator-activated receptor-γ (PPARγ) played a major function in the energy homeostasis observed in HD and that PPARγ is a potentially neuroprotective target for this disease. We report here that the transcript level of PPARγ was markedly downregulated in the cortex of a transgenic mouse model of HD (R6/2). Treatment of R6/2 mice with an agonist of PPARγ (thiazolidinedione, TZD) resulted in a beneficial effect on PPARγ. By reducing Htt aggregates and thereby ameliorating the recruitment of PPARγ into Htt aggregates, TZD treatment also elevated the availability of PPARγ level and subsequently normalized the expression of downstream genes (including PGC-1α and several mitochondrial genes) in the cortex. The above protective effects appeared to be exerted by a direct activation of the PPARγ agonist (rosiglitazone) because rosiglitazone protected a neuroblastoma cell line (N2A) from mHtt-evoked mitochondrial deficiency. Our results reveal that TZD and rosiglitazone may play a protective role in HD, and support the view that PPARγ is a potential therapeutic target in HD.
authors: Graduate Institute of Biotechnology, Chinese Culture University, Taipei 111, Taiwan. cmcphd@gmail.com
authors: Ming-Chang
authors: MC
authors: Chiang
authors: Yijuang
authors: Y
authors: Chern
authors: Rong-Nan
authors: RN
authors: Huang
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects / Q000235:genetics; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
chemical_list: D047495:PPAR gamma; D017382:Reactive Oxygen Species; D045162:Thiazolidinediones; D000077154:Rosiglitazone; C089946:2,4-thiazolidinedione