30 Sep 2004

Though it is a relatively new target of Alzheimer disease researchers, the nuclear peroxisome proliferator-activated receptor γ (PPARγ) has gained a lot of attention in a short time. (See ARF live discussion.) There are both insulin and inflammation angles that make it interesting (for example, see ARF related news story on how PPARγ agonists may help reduce Aβ load by tempering β secretase activity), and specific PPARγ agonists—the thiazolidinedione drugs pioglitazone and rosiglitazone—are already in regular use as diabetes drugs, and thus have been fast-tracked into clinical trials for AD (see ARF related news story).

Now a partner of PPARγ, called PPARγ coactivator 1α (PGC-1α), is calling attention to itself in the world of neurodegenerative disease. An article in the October 1 issue of Cell reveals that knocking out the gene for PGC-1α in mice results in a movement disorder that bears a striking resemblance to Huntington disease.

PGC-1α is a transcriptional coactivator for the several PPARs, as well as other nuclear receptors such as estrogen-related receptors and glucocorticoid receptor, among others. It is implicated in the activation of genes regulating several cellular processes, among them mitochondrial biogenesis in various tissues, thermogenesis in brown adipose tissue, and glucose synthesis (gluconeogenesis) in the liver. It is also known to be a target for proinflammatory cytokines. In their study, Bruce Spiegelman, first author Jiandie Lin, and colleagues at Harvard and several other institutions, found that PGC-1α-null mice have some expected, and some unexpected, abnormalities.

Although PGC-1α-null pups survive to parturition, only half of them live past the early postnatal period. The surviving mice are clearly not normal, particularly in terms of energy metabolism. In hepatocytes isolated from the PGC-1α-null mice, the researchers found reductions in two measures of mitochondrial respiration: total O2 consumption, and respiration due to mitochondrial proton leak. Glucose regulation was also perturbed, as shown by both in-vitro and in-vivo hormonal challenges; however, Lin and colleagues also found that a C/EBPβ pathway appears to be able to compensate to some extent, activating gluconeogenesis genes that PGC-1α also activates.

Unexpectedly, the PGC-1α-null mice are not prone to obesity and insulin resistance. This may be related to the obvious hyperactivity of the surviving mice, which in turn may be attributable to one of the few gross anatomical abnormalities from which they suffer—spongiform "lesions" in the striatum. The mice also exhibit movement problems consistent with striatal damage. "While mice deficient in PGC-1α have an apparently complex neurological disorder, the striking hyperactivity with neurodegeneration is reminiscent of HD; the latter is also accompanied by a hyperkinetic movement disorder and a progressive loss of striatal neurons," write the authors.

Although the researchers interpret the presence of reactive astrocytes and gliosis in the striatum of PGC-1α-null mice to mean that the spongiform abnormalities represent a progressive lesion process, they do not yet have evidence to confirm this. "Whether exogenous modulation of the pathways controlled by PGC-1α through genetic or pharmacological methods can improve brain function in several neurodegenerative diseases including HD remains to be determined," the authors conclude.

As Sander Houten and Johan Auwerx of the Institute of Genetic and Molecular and Cellular Biology/INSERM in Illkirch, France, discuss in their editorial accompanying the article, given that numerous cellular energy metabolism pathways are known to target PGC-1α—and that PGC-1α activates the PPARs and so many other nuclear receptors or transcription factors, and increases oxidative metabolism—it might be possible to therapeutically boost mitochondrial activity in diseases where mitochondrial deficits have been shown. Failure of mitochondrial oxidative metabolism has been linked to Parkinson disease, for example (see ARF related news story), while increases in oxidative metabolism may extend lifespan (see ARF related news story). "It is clear that research on PGC-1α has energized the entire mitochondria field and has increased the chances that strategies to turbocharge mitochondrial activity may one day translate into therapies not only for metabolic disease, but perhaps also for certain cardiac problems and neurodegenerative diseases," they write.—Hakon Heimer

Comments

1. • Elena Galea
     Universitat Autònoma de Barcelona
   • Posted: 04 Oct 2004

   The excellent study by Spiegelman and colleagues shows that the absence of PGC-1 α, a coactivator of transcription factors including the PPAR family of nuclear receptors, leads to Huntington disease-like neurodegeneration in the mouse brain. As mentioned by the authors, a key implication of the study is that “in addition to its well established role in regulating mitochondrial gene expression, PGC-1α may have an important function in the control of neuronal gene expression and function.” The study thus suggests a PGC-1α-mediated link between mitochondrial activity and neurogenesis, and opens the possibility that modulation of PGC activity could be of therapeutic interest in neurodegenerative diseases.

   These are important ideas, and it is tempting to draw a connection to neurodegenerative diseases like AD wherein: 1) mitochondrial dysfunction could be a pathogenic factor, and 2) the therapeutic benefit of treatment with PPAR agonists is currently being examined in several clinical trials. It is too premature, however, to suggest a role of PGC-1α—or lack thereof—in AD. First, the areas altered in the PGC-1α-null mouse—striatum—and the symptom—hyperactivity—are not characteristic of AD. It should be noted, however, that the study explores the consequences of PGC deficiency in brain development but not in synaptic plasticity at an older age. Second, while stimulation with PPAR agonists is being considered for AD(see ARF related news story) the already very comprehensive study by Spiegelman et al. does not reveal whether the neurodegeneration resulting from PGC-1α depletion is related to PPARs. There is thus no basis to argue that activation of PGC-1α-mediated pathways may account for the benefits derived from PPAR treatment, although this is certainly an interesting possibility to explore.

   View all comments by Elena Galea

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References

News Citations

1. Neuroimmunology Potluck: NSAIDs, Genes, and Inflammation 10 Nov 2003
2. Orlando: Early Results Hint That Insulin-Sensitizing Drug Improves Cognition 22 Nov 2002
3. Novel Cell-Based Parkinson's Model Shows Promise 22 Nov 2002
4. Caloric Restriction Increases Metabolic Rate 22 Nov 2002

Other Citations

1. ARF live discussion

Further Reading

News

1. Outlook for PPARγ Agonists Not So Rosi 13 Sep 2003
2. Neuroimmunology Potluck: NSAIDs, Genes, and Inflammation 10 Nov 2003
3. Agonist of PPARγ Cousin PPARδ Flags Cancer Caution 4 Feb 2004
4. ApoE Catalyst Conference Explores Drug Development Opportunities 20 Jul 2003
5. Orlando: Early Results Hint That Insulin-Sensitizing Drug Improves Cognition 22 Nov 2002