Peroxisome proliferator‐activated receptor‐γ cofactors in neurodegeneration

Katsouri, Loukia; Blondrath, Katrin; Sastre, Magdalena

doi:10.1002/iub.1097

Cited by 41 publications

(36 citation statements)

References 74 publications

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“…A principal cofactor and regulator of PPAR action is PPARγ-coactivator 1α (PCG-1a) (Katsouri et al, 2012). PCG-1α participates in transcriptional complexes mediating the activation of PPARγ and other nuclear receptor-responsive genes.…”

Section: Pparγmentioning

confidence: 99%

“…In MPTP treated mice, transgenic expression of PCG-1α prevented the loss of dopaminergic neurons (Mudo et al, 2012). PGC-1α levels are reduced in genetic models of PD (Katsouri et al, 2012) and in parkin mutant mice (Shin et al, 2011). PPARγ agonists have been shown to stimulate the expression of PGC-1α (Hondares 2006), providing another possible mechanism for PPARγ action in PD.…”

Section: Pparγmentioning

confidence: 99%

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Nuclear receptors in neurodegenerative diseases

Skerrett

Malm

Landreth

2014

Neurobiology of Disease

101

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Nuclear receptors have generated substantial interest in the past decade as potential therapeutic targets for the treatment of neurodegenerative disorders. Despite years of effort, effective treatments for progressive neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and ALS remain elusive, making non-classical drug targets such as nuclear receptors an attractive alternative. A substantial literature in mouse models of disease and several clinical trials have investigated the role of nuclear receptors in various neurodegenerative disorders, most prominently AD. These studies have met with mixed results, yet the majority of studies in mouse models report positive outcomes. The mechanisms by which nuclear receptor agonists affect disease pathology remain unclear. Deciphering the complex signaling underlying nuclear receptor action in neurodegenerative diseases is essential for understanding this variability in preclinical studies, and for the successful translation of nuclear receptor agonists into clinical therapies.

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Section: Pparγmentioning

confidence: 99%

Section: Pparγmentioning

confidence: 99%

Nuclear receptors in neurodegenerative diseases

Skerrett

Malm

Landreth

2014

Neurobiology of Disease

101

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“…During the past decade, the role of PPAR gamma in neurodegeneration has been established. The administration of PPAR gamma ligands has been shown to be beneficial in many NDs such as ALS, Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease and stroke [26]. PPAR gamma has been shown to have antiinflammatory and neuroprotective effects [27,28].…”

Section: Ppar Gammamentioning

confidence: 99%

“…PGC-1alpha plays a role in several neurodegenerative pathologies [26]. PGC-1al-pha protects neurons and alters disease progression in a PGC-1alpha transgenic mice crossed with SOD1 mutant G93A DL mice [55].…”

Section: Als and Ppar Gammamentioning

confidence: 99%

Amyotrophic Lateral Sclerosis: Role of the Canonical Wnt/Beta- Catenin Pathway and PPAR Gamma

Lecarpentier¹,

Vallée²

2016

Update on Amyotrophic Lateral Sclerosis

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Amyotrophic lateral sclerosis (ALS) is one of the most common adult-onset debilitating neurodegenerative diseases (NDs) which is characterized by a chronic progressive degeneration of upper and lower motor neurons, resulting in muscular atrophy, paralysis and ultimately death. It has been established that in ALS, the canonical Wnt/ beta-catenin pathway is upregulated. Peroxisome proliferator-activated receptor gamma (PPAR gamma) generally varies in opposite way compared with the Wnt/betacatenin signaling. Several studies carried out on ALS transgenic mice have shown the beneficial effects induced after treatment by PPAR agonists partly due to antiinflammatory effects induced by PPAR gamma. The coupling between the Wnt/betacatenin signaling and PPAR gamma has led to divide NDs into two classes: NDs in which the Wnt/beta-catenin pathway is upregulated whereas PPAR gamma is downregulated (ALS, Parkinson's disease, Huntington's disease and Friedreich's ataxia); and NDs in which the Wnt-beta-catenin pathway is downregulated while PPAR gamma is upregulated (Alzheimer's disease, bipolar disorder and schizophrenia).

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“…PGC-1α is abundantly expressed in high-energy demanding tissues such as adipose tissue, liver, skeletal muscle, heart, kidney, and brain (5,6) where it is involved in the regulation of glucose and lipid metabolism, oxidative phosphorylation, and mitochondrial biogenesis (4,5).…”

mentioning

confidence: 99%

PPARγ-coactivator-1α gene transfer reduces neuronal loss and amyloid-β generation by reducing β-secretase in an Alzheimer’s disease model

Katsouri

Lim

Blondrath

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

119

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Current therapies for Alzheimer's disease (AD) are symptomatic and do not target the underlying Aβ pathology and other important hallmarks including neuronal loss. PPARγ-coactivator-1α (PGC-1α) is a cofactor for transcription factors including the peroxisome proliferator-activated receptor-γ (PPARγ), and it is involved in the regulation of metabolic genes, oxidative phosphorylation, and mitochondrial biogenesis. We previously reported that PGC-1α also regulates the transcription of β-APP cleaving enzyme (BACE1), the main enzyme involved in Aβ generation, and its expression is decreased in AD patients. We aimed to explore the potential therapeutic effect of PGC-1α by generating a lentiviral vector to express human PGC-1α and target it by stereotaxic delivery to hippocampus and cortex of APP23 transgenic mice at the preclinical stage of the disease. Four months after injection, APP23 mice treated with hPGC-1α showed improved spatial and recognition memory concomitant with a significant reduction in Aβ deposition, associated with a decrease in BACE1 expression. hPGC-1α overexpression attenuated the levels of proinflammatory cytokines and microglial activation. This effect was accompanied by a marked preservation of pyramidal neurons in the CA3 area and increased expression of neurotrophic factors. The neuroprotective effects were secondary to a reduction in Aβ pathology and neuroinflammation, because wild-type mice receiving the same treatment were unaffected. These results suggest that the selective induction of PGC-1α gene in specific areas of the brain is effective in targeting AD-related neurodegeneration and holds potential as therapeutic intervention for this disease.Aβ | BACE1 | growth factor | inflammation | neurodegeneration

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Peroxisome proliferator‐activated receptor‐γ cofactors in neurodegeneration

Cited by 41 publications

References 74 publications

Nuclear receptors in neurodegenerative diseases

Nuclear receptors in neurodegenerative diseases

Amyotrophic Lateral Sclerosis: Role of the Canonical Wnt/Beta- Catenin Pathway and PPAR Gamma

PPARγ-coactivator-1α gene transfer reduces neuronal loss and amyloid-β generation by reducing β-secretase in an Alzheimer’s disease model

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