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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    • "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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    • "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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    • "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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