Peroxisome proliferator activator receptor gamma coactivator-1alpha (PGC-1α) improves motor performance and survival in a mouse model of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder characterized by progressive paralysis resulting from the death of upper and lower motor neurons. There is currently no effective pharmacological treatment for ALS, and the two approved drugs riluzole and edaravone have limited effects on the symptoms and only slightly prolong the life of patients. Therefore, the development of effective therapeutic strategies is of paramount importance. In this study, we investigated whether Miyako Island Bidens pilosa (MBP) can alleviate the neurological deterioration observed in a superoxide dismutase-1 G93A mutant transgenic mouse (G93A mouse) model of ALS. We orally administered 2 g/kg/day of MBP to G93A mice at the onset of symptoms of neurodegeneration (15 weeks old) until death. Treatment with MBP markedly prolonged the life of ALS model mice by approximately 20 days compared to that of vehicle-treated ALS model mice and significantly improved motor performance. MBP treatment prevented the reduction in SMI32 expression, a neuronal marker protein, and attenuated astrocyte (detected by GFAP) and microglia (detected by Iba-1) activation in the spinal cord of G93A mice at the end stage of the disease (18 weeks old). Our results indicate that MBP administered after the onset of ALS symptoms suppressed the inflammatory activation of microglia and astrocytes in the spinal cord of the G93A ALS model mice, thus improving their quality of life. MBP may be a potential therapeutic agent for ALS.

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Peroxisome Proliferator Activator Receptor Gamma Coactivator-1α Overexpression in Amyotrophic Lateral Sclerosis: A Tale of Two Transgenics

Biomolecules ◽

10.3390/biom10050760 ◽

2020 ◽

Vol 10 (5) ◽

pp. 760

Author(s):

Merina Varghese ◽

Wei Zhao ◽

Kyle J. Trageser ◽

Giulio M. Pasinetti

Keyword(s):

Spinal Cord ◽

Amyotrophic Lateral Sclerosis ◽

Mouse Model ◽

Whole Body ◽

Pharmacological Intervention ◽

Therapeutic Effects ◽

Peroxisome Proliferator ◽

Actin Promoter ◽

Sod1g93a Mouse ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder manifesting with upper and lower neuron loss, leading to impairments in voluntary muscle function and atrophy. Mitochondrial dysfunction in metabolism and morphology have been implicated in the pathogenesis of ALS, including atypical oxidative metabolism, reduced mitochondrial respiration in muscle, and protein aggregates in the mitochondrial outer membrane. Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) plays an essential role in the regulation of mitochondrial biogenesis, the process by which existing mitochondria grow and divide. PGC-1α has been previously reported to be downregulated in the spinal cord of individuals with ALS. Towards targeting PGC-1α as a therapeutic mechanism, we have previously reported improved motor function and survival in the SOD1G93A mouse model of ALS by neuron-specific over-expression of PGC-1α under a neuron-specific enolase (NSE) promoter. As pharmacological intervention targeting PGC-1α would result in whole-body upregulation of this transcriptional co-activator, in the current study we investigated whether global expression of PGC-1α is beneficial in a SOD1G93A mouse model, by generating transgenic mice with PGC-1α transgene expression driven by an actin promoter. Actin-PGC-1α expression levels were assayed and confirmed in spinal cord, brain, muscle, liver, kidney, and spleen. To determine the therapeutic effects of global expression of PGC-1α, wild-type, actin-PGC-1α, SOD1G93A, and actin-PGC-1α/SOD1G93A animals were monitored for weight loss, motor performance by accelerating rotarod test, and survival. Overexpression of actin-PGC-1α did not confer significant improvement in these assessed outcomes. A potential explanation for this difference is that the actin promoter may not induce levels of PGC-1α relevant to disease pathophysiology in the cells that are specifically relevant to the pathogenesis of ALS. This evidence strongly supports future therapeutic approaches that target PGC-1α primarily in neurons.

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Genetic Inactivation of Cholinergic C Bouton Output Improves Motor Performance but not Survival in a Mouse Model of Amyotrophic Lateral Sclerosis

Neuroscience ◽

10.1016/j.neuroscience.2020.07.047 ◽

2020 ◽

Vol 450 ◽

pp. 71-80

Author(s):

Eleni Konsolaki ◽

Eleftheria Koropouli ◽

Eirini Tsape ◽

Konstantinos Pothakos ◽

Laskaro Zagoraiou

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Mouse Model ◽

Motor Performance ◽

Genetic Inactivation ◽

Lateral Sclerosis

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Peroxisome Proliferator-Activated Receptor-γin Amyotrophic Lateral Sclerosis and Huntington’s Disease

PPAR Research ◽

10.1155/2008/418765 ◽

2008 ◽

Vol 2008 ◽

pp. 1-8 ◽

Cited By ~ 40

Author(s):

Mahmoud Kiaei

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Mouse Model ◽

Neurodegenerative Diseases ◽

Huntington's Disease ◽

Transgenic Mouse ◽

Transgenic Mouse Model ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

G93a Sod1 ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a debilitating and one of the most common adult-onset neurodegenerative diseases with the prevalence of about 5 per 100 000 individuals. It results in the progressive loss of upper and lower motor neurons and leads to gradual muscle weakening ultimately causing paralysis and death. ALS has an obscure cause and currently no effective treatment exists. In this review, a potentially important pathway is described that can be activated by peroxisome proliferator-activated receptor-γ(PPAR-γ) agonists and has the ability to block the neuropathological damage caused by inflammation in ALS and possibly in other neudegenerative diseases like Huntington's disease (HD). Neuroinflammation is a common pathological feature in neurodegenerative diseases. Therefore, PPAR-γagonists are thought to be neuroprotective in ALS and HD. We and others have tested the neuroprotective effect of pioglitazone (Actos), a PPAR-γagonist, in G93A SOD1 transgenic mouse model of ALS and found significant increase in survival of G93A SOD1 mice. These findings suggest that PPAR-γmay be an important regulator of neuroinflammation and possibly a new target for the development of therapeutic strategies for ALS. The involvement of PPAR-γin HD is currently under investigation, one study finds that the treatment with rosiglitazone had no protection in R6/2 transgenic mouse model of HD. PPAR-γcoactivator-1α(PGC-1α) is a transcriptional coactivator that works together with combination of other transcription factors like PPAR-γin the regulation of mitochondrial biogenesis. Therefore, PPAR-γis a possible target for ALS and HD as it functions as transcription factor that interacts with PGC-1α. In this review, the role of PPAR-γin ALS and HD is discussed based on the current literature and hypotheses.

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