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

Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA. .
Molecular Neurodegeneration (Impact Factor: 6.56). 07/2011; 6(1):51. DOI: 10.1186/1750-1326-6-51
Source: PubMed


Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that affects spinal cord and cortical motor neurons. An increasing amount of evidence suggests that mitochondrial dysfunction contributes to motor neuron death in ALS. Peroxisome proliferator-activated receptor gamma co-activator-1α (PGC-1α) is a principal regulator of mitochondrial biogenesis and oxidative metabolism.
In this study, we examined whether PGC-1α plays a protective role in ALS by using a double transgenic mouse model where PGC-1α is over-expressed in an SOD1 transgenic mouse (TgSOD1-G93A/PGC-1α). Our results indicate that PGC-1α significantly improves motor function and survival of SOD1-G93A mice. The behavioral improvements were accompanied by reduced blood glucose level and by protection of motor neuron loss, restoration of mitochondrial electron transport chain activities and inhibition of stress signaling in the spinal cord.
Our results demonstrate that PGC-1α plays a beneficial role in a mouse model of ALS, suggesting that PGC-1α may be a potential therapeutic target for ALS therapy.

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Available from: Merina Varghese, Oct 10, 2015
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    • "Moreover, a full deletion of PGC-1α in mutant SOD1 mice aggravated disease in males only, with an earlier onset and faster progression (Eschbach et al., 2013), suggesting a gender-specific loss of function of PGC-1α in patients carrying a SNP in this gene. In line with the detrimental effect of a loss of PGC-1α in ALS mice, a general overexpression of human PGC-1α preserved motor neurons and neuromuscular junctions resulting in an increased survival of these mice (Liang et al., 2011; Zhao et al., 2011). These results point towards PGC-1α as an interesting therapeutic target for ALS. "
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is characterized by the selective death of motor neurons in the motor cortex, brainstem and spinal cord. It is a neurodegenerative disorder with high genetic and phenotypic variability. In most patients, the cause of the disease is unknown. Until now, no treatment strategy has been discovered with the exception of riluzole which has a moderate effect on the disease process. While developing a new causal therapy targeting a specific disease-causing gene can have a huge effect on the disease process, only a limited number of ALS patients will benefit from such a therapy. Alternatively, pathogenic processes that are common in ALS patients with different etiology can also be targeted. The effect of such a modifying treatment will be smaller, but the target population will be larger as more ALS patients could benefit. In this review, we summarize the evidence for the involvement of different biological processes in the pathogenesis of ALS and will discuss how strategies influencing these processes can be translated into new therapeutic approaches. In order to further improve this translational step, there is an urgent need for a better understanding of the underlying mechanism(s), for new ALS animal models and for rigorous protocols to perform preclinical studies.
    Experimental Neurology 12/2014; 262. DOI:10.1016/j.expneurol.2014.07.001 · 4.70 Impact Factor
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    • "Other authors reported that increasing the expression of PGC-1α selectively both in neurons or in muscle cells of ALS mice model makes it possible to maintain mitochondrial biogenesis and activity through end-stage, to delay muscle atrophy, and to significantly improve muscle functions (Da Cruz et al., 2012; Zhao et al., 2011). Nevertheless, mice survival was extended only when PGC-1α is increased in neurons, suggesting that muscle is not a primary target of mutant SOD1-mediated toxicity (Da Cruz et al., 2012; Zhao et al., 2011). It is also interesting to highlight that PGC- 1α activity is sex-dependent, since its deficiency accelerated disease onset only in male mice (Eschbach et al., 2013). "
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    ABSTRACT: Amyotrophic Lateral Sclerosis (ALS) is the most common form of adult-onset motor neuron disease. It is now considered a multi-factorial and multi-systemic disorder in which alterations of the crosstalk between neuronal and non-neuronal cell types might influence the course of the disease. In this review, we will provide evidence that dysfunctions of affected muscle cells are not only a marginal consequence of denervation associated to motor neurons loss, but a direct consequence of cell muscle toxicity of mutant SOD1. In muscle, the misfolded state of mutant SOD1 protein, unlike in motor neurons, does not appear to have direct effects on protein aggregation and mitochondrial functionality. Muscle cells are, in fact, more capable than motor neurons to handle misfolded proteins, suggesting that mutant SOD1 toxicity in muscle is not mediated by classical mechanisms of intracellular misfolded proteins accumulation. Several recent works indicate that a higher activation of molecular chaperones and degradative systems is present in muscle cells, which for this reason are possibly able to better manage misfolded mutant SOD1. However, several alterations in gene expression and regenerative potential of skeletal muscles have also been reported as a consequence of the expression of mutant SOD1 in muscle. Whether these changes in muscle cells are causative of ALS or a consequence of motor neuron alterations is not yet clear, but their elucidation is very important, since the understanding of the mechanisms involved in mutant SOD1 toxicity in muscle may facilitate the design of treatments directed toward this specific tissue to treat ALS or at least to delay disease progression.
    Neurochemistry International 11/2014; 79. DOI:10.1016/j.neuint.2014.10.007 · 3.09 Impact Factor
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    • "s activated by several converging pathways including cAMP and cytokines ( Puigserver and Spiegelman , 2003 ) and reduced PCG - 1α mRNA levels have been described in ALS patients ( Thau et al . , 2012 ) . Overexpressing PCG - 1α in the SOD1 G93A model improves motor function and prolongs survival possibly by restoring close to normal ETC activity ( Zhao et al . , 2011 ) . Interestingly , PCG - 1α / G93A animals also show an increased expression of astrocytic GLT - 1 glutamate transporters that may have been the ultimate cause of neuroprotection seen in this model . Whether this is a primary or secondary event is not known and the relation to enhanced mitochondrial func - tion is unclear . In the cont"
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by the selective death of upper and lower motor neurons which ultimately leads to paralysis and ultimately death. Pathological changes in ALS are closely associated with pronounced and progressive changes in mitochondrial morphology, bioenergetics and calcium homeostasis. Converging evidence suggests that impaired mitochondrial function could be pivotal in the rapid neurodegeneration of this condition. In this review, we provide an update of recent advances in understanding mitochondrial biology in the pathogenesis of ALS and highlight the therapeutic value of pharmacologically targeting mitochondrial biology to slow disease progression.Linked ArticlesThis article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit
    British Journal of Pharmacology 04/2014; 171(8). DOI:10.1111/bph.12476 · 4.84 Impact Factor
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