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Lin J, Wu PH, Tarr PT, Lindenberg KS, St-Pierre J, Zhang CY, Mootha VK, Jäger S, Vianna CR, Reznick RM, Cui L, Manieri M, Donovan MX, Wu Z, Cooper MP, Fan MC, Rohas LM, Zavacki AM, Cinti S, Shulman GI, Lowell BB, Krainc D, Spiegelman BM.
Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1alpha null mice. Cell.
2004 Oct 1;119(1):121-35.
PubMed Abstract
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Comments on Paper and Primary News |
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Primary News: PPARγ Partner PGC-1α Linked to Huntington Disease-Like Symptoms
Comment by: Elena Galea
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Submitted 4 October 2004
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Posted 4 October 2004
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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,...
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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.
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REAGENTS/MATERIAL:
PGC-1a+/− mice were developed through transgenic expression of cre recombinase under the control of ZP3 promoter. Homologous recombination and cre-mediated excision events were confirmed by hybridization and PCR analysis of genomic DNA isolated from PGC-1a+/+, PGC-1a+/−, and PGC-1a−/− mice.
Mouse brain tissues were stained with antibodies against glial fibrillary acidic protein (GFAP, polyclonal antibody 1:200; Dako, Hamburg, Germany) as an astrocyte marker and against neurofilament 200 kDa (monoclonal antibody 1:50; Sigma) to label axons.
For detection of PGC-1a protein, nuclear extracts prepared from brown fat were analyzed by immunoblotting using mouse polyclonal antibodies raised against the purified C terminus of PGC-1a. Muscle AMPK was detected with antibodies that recognize total AMPK (#07–181, Upstate Biotechnology) or phosphorylated AMPK (2531, Cell Signaling Technology). ACC phosphorylation was detected using a phospho-ACC-specific antibody (3661, Cell Signaling Technology).
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