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

Chiang, Ming‐Chang; Cheng, Yi-Chuan; Nicol, Christopher J.B.; Lin, Kuan‐Hung; Yen, Chia‐Hui; Chen, Shiang-Jiuun; Huang, Rong‐Nan

doi:10.1016/j.yexcr.2015.09.005

Cited by 33 publications

(29 citation statements)

References 77 publications

(117 reference statements)

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“…Rosiglitazone also significantly increased survival in N2A cells expressing mutant huntingtin, while also upregulating the expression of PPARγ, PGC1α, NRF-1, TFAM and improving mitochondrial function in mutant cells. Rosiglitazone treatment also normalized endoplasmic reticulum stress sensors Bip, CHOP and ASK1 and significantly reduced mutant huntingtin aggregates that included ubiquitin and heat shock factor 1 and increased the levels of the functional ubiquitin-proteasome system and heat shock protein 27/70 [28].…”

Section: Mechanisms Of Protection By Pparγ In Neurodegenerative Diseasesmentioning

confidence: 90%

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

Corona

Duchen

2016

Free Radical Biology and Medicine

181

127

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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.

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Section: Mechanisms Of Protection By Pparγ In Neurodegenerative Diseasesmentioning

confidence: 90%

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

Corona

Duchen

2016

Free Radical Biology and Medicine

181

127

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“…In vitro , 10 – 13 increase cell viability and improve neuronal function in models of ischemic injury, 139 Alzheimer disease, 140 Huntington’s disease, 141–142 and multiple sclerosis. 143 Similarly, in animal models of neurodegenerative diseases, 10 and 11 improve both cellular and behavioral markers of neurological function.…”

Section: Transcription Factor Modulatorsmentioning

confidence: 99%

Development of Therapeutics That Induce Mitochondrial Biogenesis for the Treatment of Acute and Chronic Degenerative Diseases

2016

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Mitochondria have various roles in cellular metabolism and homeostasis. Because mitochondrial dysfunction is associated with many acute and chronic degenerative diseases, mitochondrial biogenesis (MB) is a therapeutic target for treating such diseases. Here, we review the role of mitochondrial dysfunction in acute and chronic degenerative diseases and the cellular signaling pathways by which MB is induced. We then review existing work describing the development and application of drugs that induce MB in vitro and in vivo. In particular, we discuss natural products and modulators of transcription factors, kinases, cyclic nucleotides, and G protein-coupled receptors.

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“…Putative binding factors were predicted using SpaMo directly from the DREME suite software package and are listed in the tables shown with their putative transcription factors. The literature (Ref) links of each TF to psychiatric disorders are shown: Scz (schizophrenia); BP (Bipolar Disorder); MDD (Major Depressive Disorder); Epi (Epilepsy); ND (Neuronal Differentiation); OCD (Obsessive Compulsive Disorder) (Aston et al, 2005; Basmanav et al, 2015; Butts et al, 2014; Castilhos et al, 2014; Chen et al, 2014b; Chiang et al, 2015; Forero et al, 2016; Forrest et al, 2013; Goes et al, 2015; Grados et al, 2014; Gurung and Prata, 2015; Hattori et al, 2014; Johansson et al, 2016; Jukic et al, 2015; Keyes et al, 2015; Kim et al, 2014; Le-Niculescu et al, 2009; Lisowski et al, 2013; Mencarelli et al, 2008; Nestadt et al, 2012; Rivolta et al, 2014; Rotheram-Fuller et al, 2010; Schlaudraff et al, 2014; Shi et al, 2016; Wang et al, 2014; Wei et al, 2015; Wockner et al, 2014). …”

Section: Figurementioning

confidence: 99%

Sex-specific hippocampal 5-hydroxymethylcytosine is disrupted in response to acute stress

Papale

Madrid

et al. 2016

Neurobiology of Disease

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Environmental stress is among the most important contributors to increased susceptibility to develop psychiatric disorders. While it is well known that acute environmental stress alters gene expression, the molecular mechanisms underlying these changes remain largely unknown. 5-hydroxymethylcytosine (5hmC) is a novel environmentally sensitive epigenetic modification that is highly enriched in neurons and is associated with active neuronal transcription. Recently, we reported a genome-wide disruption of hippocampal 5hmC in male mice following acute stress that was correlated to altered transcript levels of genes in known stress related pathways. Since sex-specific endocrine mechanisms respond to environmental stimulus by altering the neuronal epigenome, we examined the genome-wide profile of hippocampal 5hmC in female mice following exposure to acute stress and identified 363 differentially hydroxymethylated regions (DhMRs) linked to known (e.g., Nr3c1 and Ntrk2) and potentially novel genes associated with stress response and psychiatric disorders. Integration of hippocampal expression data from the same female mice found stress-related hydroxymethylation correlated to altered transcript levels. Finally, characterization of stress-induced sex-specific 5hmC profiles in the hippocampus revealed 778 sex-specific acute stress-induced DhMRs some of which were correlated to altered transcript levels that produce sex-specific isoforms in response to stress. Together, the alterations in 5hmC presented here provide a possible molecular mechanism for the adaptive sex-specific response to stress that may augment the design of novel therapeutic agents that will have optimal effectiveness in each sex.

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

Cited by 33 publications

References 77 publications

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

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

Development of Therapeutics That Induce Mitochondrial Biogenesis for the Treatment of Acute and Chronic Degenerative Diseases

Sex-specific hippocampal 5-hydroxymethylcytosine is disrupted in response to acute stress

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